chr2-214953891-G-A

Position:

chr2-214953891-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_173076.3(ABCA12):c.6610C>T(p.Arg2204Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

ABCA12
NM_173076.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.40

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 made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-214953891-G-A is Pathogenic according to our data. Variant chr2-214953891-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-214953891-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA12	NM_173076.3 linkuse as main transcript	c.6610C>T	p.Arg2204Ter	stop_gained	44/53	ENST00000272895.12	NP_775099.2
SNHG31	NR_110292.1 linkuse as main transcript	n.444+5944G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA12	ENST00000272895.12 linkuse as main transcript	c.6610C>T	p.Arg2204Ter	stop_gained	44/53	1	NM_173076.3	ENSP00000272895	P1	Q86UK0-1
SNHG31	ENST00000670391.1 linkuse as main transcript	n.438-7919G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151912

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461686

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151912

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74166

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000322

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 19, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2862). This premature translational stop signal has been observed in individuals with autosomal recessive congenital ichthyosis (PMID: 15756637, 30916489, 32293521). This variant is present in population databases (rs137853289, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg2204*) in the ABCA12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA12 are known to be pathogenic (PMID: 20672373). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32293521, 15756637, 30916489) -

Autosomal recessive congenital ichthyosis 4B

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The c.6610C>T;(p.Arg2204Ter) variant creates a premature stop codon at amino acid position Arg2204, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). Recently, the variant c.6610C>T; (p.Arg2204*) has been reported by (MontalvÃ¡n-SuÃ¡rez et al, 2019), in the compound heterozygous state, in a 4 years old boy with harlequin ichthyosis, This variant is reported with the allele frequency (00.003198%) in the gnomad and novel in 1000 genome database. It has been submitted to ClinVar as Pathogenic. The nucleotide change in ABCA12 is predicted as conserved by GERP++ and PhyloP. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2005	- -

Autosomal recessive congenital ichthyosis 4A

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Breda Genetics srl

May 06, 2020

The variant c.6610C>T (p.Arg2204*) in the ABCA12 gene is reported as pathogenic for ichthyosis, congenital, autosomal recessive 4B in ClinVar (Variation ID: 2862) and as affects function in the Global Variome shared LOVD database v.3.0. The variant creates a premature stop codon at amino acid position Arg2204, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant is reported with an estimated allele frequency of 0.00003198 in gnomAD genomes, with no homozygous individuals reported. The variant c.6610C>T (p.Arg2204*), also known as p.Arg2003*, has been firstly reported by Kelsell et al. (2005) in the homozygous state in an African American child with harlequin ichthyosis (PMID: 15756637). Recently, the variant c.6610C>T (p.Arg2204*) has been reported by MontalvÃ¡n-SuÃ¡rez et al. (2019), in the compound heterozygous state, in a 4 years old Ecuadorian boy with harlequin ichthyosis (PMID: 30916489). -

Lamellar ichthyosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 20, 2023

Variant summary: ABCA12 c.6610C>T (p.Arg2204X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250986 control chromosomes (gnomAD v2.1, Exomes dataset). c.6610C>T has been reported in the literature in individuals affected with Lamellar Ichthyosis (e.g., Montalvan-Suarez_2019). These data suggest the variant is very likely to be associated with disease. The following publication was ascertained in the context of this evaluation (PMID: 30916489). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

0.14

Eigen_PC

Benign

-0.044

FATHMM_MKL

Uncertain

0.94

MutationTaster

Benign

1.0

A;A

Vest4

0.95

GERP RS

2.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over