2-215011647-T-C

Variant names:

• chr2-215011647-T-C
• rs10198064
• NM_173076.3:c.2124A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_173076.3(ABCA12):​c.2124A>G​(p.Ala708Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,613,406 control chromosomes in the GnomAD database, including 24,124 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (8799 hom., cov: 32)
  • Exomes 𝑓: 0.11 (15325 hom.)
• Consequence: ABCA12 NM_173076.3 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.716

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]

ENSG00000227769 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 2-215011647-T-C is Benign according to our data. Variant chr2-215011647-T-C is described in ClinVar as [Benign]. Clinvar id is 262823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215011647-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.716 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA12	NM_173076.3	c.2124A>G	p.Ala708Ala	splice_region_variant, synonymous_variant	Exon 17 of 53	ENST00000272895.12	NP_775099.2
ABCA12	NM_015657.4	c.1170A>G	p.Ala390Ala	splice_region_variant, synonymous_variant	Exon 9 of 45		NP_056472.2
ABCA12	XM_011510951.3	c.2124A>G	p.Ala708Ala	splice_region_variant, synonymous_variant	Exon 17 of 53		XP_011509253.1
ABCA12	NR_103740.2	n.2566A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 18 of 55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA12	ENST00000272895.12	c.2124A>G	p.Ala708Ala	splice_region_variant, synonymous_variant	Exon 17 of 53	1	NM_173076.3	ENSP00000272895.7
ABCA12	ENST00000389661.4	c.1170A>G	p.Ala390Ala	splice_region_variant, synonymous_variant	Exon 9 of 45	1		ENSP00000374312.4
ENSG00000227769	ENST00000617699.1	n.29-1409T>C		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37782 AN: 151928 Hom.: 8762 Cov.: 32

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.0473

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.0328

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.0880

Gnomad OTH AF: 0.239

GnomAD3 exomes AF: 0.150 AC: 37605 AN: 251246 Hom.: 5423 AF XY: 0.138 AC XY: 18770 AN XY: 135808

Gnomad AFR exome AF: 0.624

Gnomad AMR exome AF: 0.254

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.0414

Gnomad SAS exome AF: 0.161

Gnomad FIN exome AF: 0.0340

Gnomad NFE exome AF: 0.0886

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.111 AC: 161661 AN: 1461360 Hom.: 15325 Cov.: 36 AF XY: 0.110 AC XY: 80188 AN XY: 727008

Gnomad4 AFR exome AF: 0.634

Gnomad4 AMR exome AF: 0.257

Gnomad4 ASJ exome AF: 0.127

Gnomad4 EAS exome AF: 0.0552

Gnomad4 SAS exome AF: 0.165

Gnomad4 FIN exome AF: 0.0331

Gnomad4 NFE exome AF: 0.0879

Gnomad4 OTH exome AF: 0.139

GnomAD4 genome AF: 0.249 AC: 37872 AN: 152046 Hom.: 8799 Cov.: 32 AF XY: 0.245 AC XY: 18239 AN XY: 74320

Gnomad4 AFR AF: 0.613

Gnomad4 AMR AF: 0.264

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.0472

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.0328

Gnomad4 NFE AF: 0.0879

Gnomad4 OTH AF: 0.236

Alfa AF: 0.149 Hom.: 3932

Bravo AF: 0.281

Asia WGS AF: 0.124 AC: 433 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.102

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

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

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital ichthyosis of skin Benign:1

Jan 12, 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
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.20
DANN	Benign	0.51

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: rs10198064; hg19: chr2-215876371;