2-215011442-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_173076.3(ABCA12):c.2329T>A(p.Ser777Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 1,600,786 control chromosomes in the GnomAD database, including 799,807 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S777F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 1.0 ( 75879 hom., cov: 33)

Exomes 𝑓: 1.0 ( 723928 hom. )

Consequence

ABCA12
NM_173076.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.35

Publications

28 publications found

Variant links:

Genes affected

ABCA12 (HGNC:14637): (ATP binding cassette subfamily A member 12) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, and White). This encoded protein is a member of the ABC1 subfamily, which is the only major ABC subfamily found exclusively in multicellular eukaryotes. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ABCA12 Gene-Disease associations (from GenCC):

autosomal recessive congenital ichthyosis 4B
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, PanelApp Australia, Orphanet, G2P
autosomal recessive congenital ichthyosis 4A
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
congenital non-bullous ichthyosiform erythroderma
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
lamellar ichthyosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ABCA12 links:

ENSG00000227769 (HGNC:):

ENSG00000227769 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.4789233E-6).

BP6

Variant 2-215011442-A-T is Benign according to our data. Variant chr2-215011442-A-T is described in ClinVar as [Benign]. Clinvar id is 262824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA12	NM_173076.3 link	c.2329T>A	p.Ser777Thr	missense_variant	Exon 17 of 53	ENST00000272895.12	NP_775099.2	Q86UK0-1B3KVV3
ABCA12	NM_015657.4 link	c.1375T>A	p.Ser459Thr	missense_variant	Exon 9 of 45		NP_056472.2	Q86UK0-2B3KVV3
ABCA12	XM_011510951.3 link	c.2329T>A	p.Ser777Thr	missense_variant	Exon 17 of 53		XP_011509253.1
ABCA12	NR_103740.2 link	n.2771T>A		non_coding_transcript_exon_variant	Exon 18 of 55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCA12	ENST00000272895.12 link	c.2329T>A	p.Ser777Thr	missense_variant	Exon 17 of 53	1	NM_173076.3	ENSP00000272895.7	Q86UK0-1
ABCA12	ENST00000389661.4 link	c.1375T>A	p.Ser459Thr	missense_variant	Exon 9 of 45	1		ENSP00000374312.4	Q86UK0-2
ENSG00000227769	ENST00000617699.1 link	n.29-1614A>T		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.998

AC:

151936

AN:

152234

Hom.:

75821

Cov.:

show subpopulations

Gnomad AFR

AF:

0.993

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.999

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.997

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.999

GnomAD2 exomes

AF:

1.00

AC:

249510

AN:

249634

AF XY:

1.00

show subpopulations

Gnomad AFR exome

AF:

0.993

Gnomad AMR exome

AF:

1.00

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

1.00

GnomAD4 exome

AF:

1.00

AC:

1448145

AN:

1448434

Hom.:

723928

Cov.:

AF XY:

1.00

AC XY:

721371

AN XY:

721500

show subpopulations

African (AFR)

AF:

0.993

AC:

32858

AN:

33074

American (AMR)

AF:

1.00

AC:

44640

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26030

AN:

26030

East Asian (EAS)

AF:

1.00

AC:

39622

AN:

39622

South Asian (SAS)

AF:

1.00

AC:

85925

AN:

85928

European-Finnish (FIN)

AF:

1.00

AC:

53342

AN:

53342

Middle Eastern (MID)

AF:

1.00

AC:

5737

AN:

5738

European-Non Finnish (NFE)

AF:

1.00

AC:

1100068

AN:

1100086

Other (OTH)

AF:

0.999

AC:

59923

AN:

59956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.998

AC:

152053

AN:

152352

Hom.:

75879

Cov.:

AF XY:

0.998

AC XY:

74365

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.993

AC:

41297

AN:

41584

American (AMR)

AF:

1.00

AC:

15295

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5192

AN:

5192

South Asian (SAS)

AF:

1.00

AC:

4825

AN:

4826

European-Finnish (FIN)

AF:

1.00

AC:

10616

AN:

10616

Middle Eastern (MID)

AF:

0.997

AC:

293

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68041

AN:

68042

Other (OTH)

AF:

0.999

AC:

2110

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.963

Hom.:

53507

Bravo

AF:

0.998

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

1.00

AC:

3854

ESP6500AA

AF:

0.993

AC:

4377

ESP6500EA

AF:

1.00

AC:

8598

ExAC

AF:

0.999

AC:

121330

Asia WGS

AF:

0.999

AC:

3473

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal recessive congenital ichthyosis 4A

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital ichthyosis of skin

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive congenital ichthyosis 4B

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.26

(source)

DANN

Benign

0.13

DEOGEN2

Benign

0.048

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0039

LIST_S2

Benign

0.30

T;T

MetaRNN

Benign

0.0000015

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.

PhyloP100

-1.4

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.67

N;N

REVEL

Benign

0.024

Sift

Benign

0.40

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.0

B;B

Vest4

0.028

MPC

0.17

ClinPred

0.0085

GERP RS

-2.9

Varity_R

0.041

gMVP

0.45

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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2-215011442-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over