Genetic Variant ABCA12:p.Asp2365Asn (chr2-214948607-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_173076.3(ABCA12):c.7093G>A(p.Asp2365Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0279 in 1,613,738 control chromosomes in the GnomAD database, including 802 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 69 hom., cov: 31)

Exomes 𝑓: 0.028 ( 733 hom. )

Consequence

ABCA12
NM_173076.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:9

Conservation

PhyloP100: 2.53

Publications

21 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 links:

SNHG31 (HGNC:54196): (small nucleolar RNA host gene 31)

SNHG31 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=0.0023857653).

BP6

Variant 2-214948607-C-T is Benign according to our data. Variant chr2-214948607-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 2861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0228 (3468/152196) while in subpopulation NFE AF = 0.029 (1969/68006). AF 95% confidence interval is 0.0279. There are 69 homozygotes in GnomAd4. There are 1841 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 69 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173076.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ABCA12	NM_173076.3	MANE Select	c.7093G>A	p.Asp2365Asn	missense	Exon 47 of 53	NP_775099.2
ABCA12	NM_015657.4		c.6139G>A	p.Asp2047Asn	missense	Exon 39 of 45	NP_056472.2
ABCA12	NR_103740.2		n.7591G>A		non_coding_transcript_exon	Exon 49 of 55

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCA12	ENST00000272895.12	TSL:1 MANE Select	c.7093G>A	p.Asp2365Asn	missense	Exon 47 of 53	ENSP00000272895.7	Q86UK0-1
ABCA12	ENST00000389661.4	TSL:1	c.6139G>A	p.Asp2047Asn	missense	Exon 39 of 45	ENSP00000374312.4	Q86UK0-2
SNHG31	ENST00000607412.2	TSL:2	n.473+660C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0228

AC:

3471

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00560

Gnomad AMI

AF:

0.0363

Gnomad AMR

AF:

0.0126

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0168

Gnomad FIN

AF:

0.0853

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0289

Gnomad OTH

AF:

0.0167

GnomAD2 exomes

AF:

0.0279

AC:

7024

AN:

251338

AF XY:

0.0273

show subpopulations

Gnomad AFR exome

AF:

0.00468

Gnomad AMR exome

AF:

0.0279

Gnomad ASJ exome

AF:

0.00774

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0800

Gnomad NFE exome

AF:

0.0311

Gnomad OTH exome

AF:

0.0224

GnomAD4 exome

AF:

0.0284

AC:

41537

AN:

1461542

Hom.:

733

Cov.:

AF XY:

0.0283

AC XY:

20586

AN XY:

727076

show subpopulations

African (AFR)

AF:

0.00409

AC:

137

AN:

33472

American (AMR)

AF:

0.0252

AC:

1128

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00708

AC:

185

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39680

South Asian (SAS)

AF:

0.0160

AC:

1382

AN:

86254

European-Finnish (FIN)

AF:

0.0753

AC:

4024

AN:

53412

Middle Eastern (MID)

AF:

0.00538

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0299

AC:

33291

AN:

1111720

Other (OTH)

AF:

0.0225

AC:

1357

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

1950

3900

5849

7799

9749

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1204

2408

3612

4816

6020

<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:

0.0228

AC:

3468

AN:

152196

Hom.:

Cov.:

AF XY:

0.0247

AC XY:

1841

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.00559

AC:

232

AN:

41536

American (AMR)

AF:

0.0125

AC:

191

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00662

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.0166

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0853

AC:

904

AN:

10598

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0290

AC:

1969

AN:

68006

Other (OTH)

AF:

0.0166

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

176

353

529

706

882

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0256

Hom.:

266

Bravo

AF:

0.0171

TwinsUK

AF:

0.0280

AC:

104

ALSPAC

AF:

0.0252

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0259

AC:

223

ExAC

AF:

0.0278

AC:

3369

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0252

EpiControl

AF:

0.0251

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive congenital ichthyosis 4B (3)

not provided (3)

not specified (2)

Autosomal recessive congenital ichthyosis 4B;C1832550:Autosomal recessive congenital ichthyosis 4A (1)

Congenital ichthyosis of skin (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

Eigen

Benign

-0.024

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0024

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.6

PhyloP100

2.5

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.34

Sift

Benign

0.28

Sift4G

Benign

0.25

Polyphen

0.91

Vest4

0.093

MPC

0.61

ClinPred

0.026

GERP RS

4.6

Varity_R

0.15

gMVP

0.53

Mutation Taster

=85/15

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over