2-214948607-C-T

Variant names:

• chr2-214948607-C-T
• rs726070
• NM_173076.3:c.7093G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:9
• Conservation: PhyloP100: 2.53
• Publications: 21 publications found

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]

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

ACMG classification

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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

Selected	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
	ABCA12	ENST00000389661.4	TSL:1	c.6139G>A	p.Asp2047Asn	missense	Exon 39 of 45	ENSP00000374312.4
	SNHG31	ENST00000607412.2	TSL:2	n.473+660C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3471 AN: 152078 Hom.: 69 Cov.: 31

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

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.: 32 AF XY: 0.0283 AC XY: 20586 AN XY: 727076

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: 2 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: 31 AN: 5764

European-Non Finnish (NFE) AF: 0.0299 AC: 33291 AN: 1111720

Other (OTH) AF: 0.0225 AC: 1357 AN: 60384

GnomAD4 genome AF: 0.0228 AC: 3468 AN: 152196 Hom.: 69 Cov.: 31 AF XY: 0.0247 AC XY: 1841 AN XY: 74394

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: 23 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4822

European-Finnish (FIN) AF: 0.0853 AC: 904 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0290 AC: 1969 AN: 68006

Other (OTH) AF: 0.0166 AC: 35 AN: 2112

Alfa AF: 0.0256 Hom.: 266

Bravo AF: 0.0171

TwinsUK AF: 0.0280 AC: 104

ALSPAC AF: 0.0252 AC: 97

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0259 AC: 223

ExAC AF: 0.0278 AC: 3369

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0252

EpiControl AF: 0.0251

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive congenital ichthyosis 4B Pathogenic:1 Benign:2

May 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 24, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

not provided Benign:3

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCA12: BP4, BS1, BS2; SNHG31: BS1, BS2

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Autosomal recessive congenital ichthyosis 4B;C1832550:Autosomal recessive congenital ichthyosis 4A Benign:1

Oct 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.024
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0024	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.34
Sift	Benign	0.28	T
Sift4G	Benign	0.25	T
Polyphen		0.91	P
Vest4		0.093
MPC		0.61
ClinPred		0.026	T
GERP RS		4.6
Varity_R		0.15
gMVP		0.53
Mutation Taster		=85/15	polymorphism (auto)

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

Other links and lift over

dbSNP: rs726070; hg19: chr2-215813331; COSMIC: COSV107251386;