2-215045850-G-C

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.859C>G(p.Arg287Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00657 in 1,612,644 control chromosomes in the GnomAD database, including 576 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. R287Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.035 ( 302 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 274 hom. )

Consequence

ABCA12
NM_173076.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.83

Publications

12 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=0.001654923).

BP6

Variant 2-215045850-G-C is Benign according to our data. Variant chr2-215045850-G-C is described in ClinVar as Benign. ClinVar VariationId is 235771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ABCA12	NM_173076.3 link	c.859C>G	p.Arg287Gly	missense_variant	Exon 7 of 53	ENST00000272895.12	NP_775099.2
ABCA12	XM_011510951.3 link	c.859C>G	p.Arg287Gly	missense_variant	Exon 7 of 53		XP_011509253.1
ABCA12	NR_103740.2 link	n.1301C>G		non_coding_transcript_exon_variant	Exon 8 of 55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ABCA12	ENST00000272895.12 link	c.859C>G	p.Arg287Gly	missense_variant	Exon 7 of 53	1	NM_173076.3	ENSP00000272895.7
ENSG00000227769	ENST00000626134.2 link	n.404+1333G>C		intron_variant	Intron 4 of 4	5
ENSG00000227769	ENST00000626771.1 link	n.338+1333G>C		intron_variant	Intron 4 of 5	5
ENSG00000227769	ENST00000628464.2 link	n.1021+1333G>C		intron_variant	Intron 7 of 8	5

Frequencies

GnomAD3 genomes

AF:

0.0352

AC:

5345

AN:

151920

Hom.:

300

Cov.:

show subpopulations

Gnomad AFR

AF:

0.120

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0171

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.0311

GnomAD2 exomes

AF:

0.00922

AC:

2306

AN:

250144

AF XY:

0.00673

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.00605

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000416

Gnomad OTH exome

AF:

0.00608

GnomAD4 exome

AF:

0.00359

AC:

5242

AN:

1460606

Hom.:

274

Cov.:

AF XY:

0.00302

AC XY:

2197

AN XY:

726630

show subpopulations

African (AFR)

AF:

0.120

AC:

4001

AN:

33274

American (AMR)

AF:

0.00773

AC:

345

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39628

South Asian (SAS)

AF:

0.000244

AC:

AN:

86166

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53234

Middle Eastern (MID)

AF:

0.00729

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000299

AC:

332

AN:

1111466

Other (OTH)

AF:

0.00831

AC:

501

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.422

Heterozygous variant carriers

221

442

663

884

1105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

256

384

512

640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0352

AC:

5359

AN:

152038

Hom.:

302

Cov.:

AF XY:

0.0336

AC XY:

2500

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.120

AC:

4992

AN:

41472

American (AMR)

AF:

0.0170

AC:

260

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000208

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000588

AC:

AN:

67972

Other (OTH)

AF:

0.0308

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

243

485

728

970

1213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00311

Hom.:

Bravo

AF:

0.0416

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.128

AC:

563

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.0118

AC:

1427

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.000655

EpiControl

AF:

0.000534

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 22, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Congenital ichthyosis of skin

Benign:1

Mar 06, 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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Benign

-0.043

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

3.8

PrimateAI

Benign

0.20

PROVEAN

Benign

-1.5

REVEL

Benign

0.24

Sift

Uncertain

0.014

Sift4G

Uncertain

0.027

Vest4

0.31

ClinPred

0.029

GERP RS

5.6

Varity_R

0.18

gMVP

0.26

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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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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