NM_173076.3:c.4126T>C

Variant names:

• chr2-214986579-A-G
• rs34351934
• NM_173076.3:c.4126T>C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_173076.3(ABCA12):​c.4126T>C​(p.Leu1376Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,613,664 control chromosomes in the GnomAD database, including 15,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3909 hom., cov: 32)
  • Exomes 𝑓: 0.11 (11808 hom.)
• Consequence: ABCA12 NM_173076.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.97

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-214986579-A-G is Benign according to our data. Variant chr2-214986579-A-G is described in ClinVar as [Benign]. Clinvar id is 262827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-214986579-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA12	NM_173076.3	c.4126T>C	p.Leu1376Leu	synonymous_variant	Exon 28 of 53	ENST00000272895.12	NP_775099.2
ABCA12	NM_015657.4	c.3172T>C	p.Leu1058Leu	synonymous_variant	Exon 20 of 45		NP_056472.2
ABCA12	XM_011510951.3	c.4135T>C	p.Leu1379Leu	synonymous_variant	Exon 28 of 53		XP_011509253.1
ABCA12	NR_103740.2	n.4624T>C		non_coding_transcript_exon_variant	Exon 30 of 55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA12	ENST00000272895.12	c.4126T>C	p.Leu1376Leu	synonymous_variant	Exon 28 of 53	1	NM_173076.3	ENSP00000272895.7
ABCA12	ENST00000389661.4	c.3172T>C	p.Leu1058Leu	synonymous_variant	Exon 20 of 45	1		ENSP00000374312.4

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28163 AN: 152014 Hom.: 3891 Cov.: 32

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.0441

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.0341

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.0964

Gnomad OTH AF: 0.196

GnomAD3 exomes AF: 0.137 AC: 34549 AN: 251318 Hom.: 3550 AF XY: 0.131 AC XY: 17788 AN XY: 135828

Gnomad AFR exome AF: 0.387

Gnomad AMR exome AF: 0.249

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.0377

Gnomad SAS exome AF: 0.162

Gnomad FIN exome AF: 0.0358

Gnomad NFE exome AF: 0.0957

Gnomad OTH exome AF: 0.146

GnomAD4 exome AF: 0.111 AC: 162906 AN: 1461532 Hom.: 11808 Cov.: 34 AF XY: 0.112 AC XY: 81478 AN XY: 727078

Gnomad4 AFR exome AF: 0.389

Gnomad4 AMR exome AF: 0.251

Gnomad4 ASJ exome AF: 0.146

Gnomad4 EAS exome AF: 0.0499

Gnomad4 SAS exome AF: 0.166

Gnomad4 FIN exome AF: 0.0350

Gnomad4 NFE exome AF: 0.0967

Gnomad4 OTH exome AF: 0.132

GnomAD4 genome AF: 0.186 AC: 28221 AN: 152132 Hom.: 3909 Cov.: 32 AF XY: 0.183 AC XY: 13603 AN XY: 74380

Gnomad4 AFR AF: 0.375

Gnomad4 AMR AF: 0.241

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.0440

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.0341

Gnomad4 NFE AF: 0.0964

Gnomad4 OTH AF: 0.194

Alfa AF: 0.148 Hom.: 1158

Bravo AF: 0.209

Asia WGS AF: 0.107 AC: 373 AN: 3478

EpiCase AF: 0.112

EpiControl AF: 0.109

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 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

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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
BayesDel_noAF	Benign	-0.44
CADD	Benign	6.5
DANN	Benign	0.81

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

LitVar

Other links and lift over

dbSNP: rs34351934; hg19: chr2-215851303; COSMIC: COSV55958194;