17-33025976-G-A

Position:

• chr17-33025976-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_183377.2(ASIC2):​c.1145C>T​(p.Ala382Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ASIC2 NM_183377.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.05

Genes affected

ASIC2 (HGNC:99): (acid sensing ion channel subunit 2) This gene encodes a member of the degenerin/epithelial sodium channel (DEG/ENaC) superfamily. The members of this family are amiloride-sensitive sodium channels that contain intracellular N and C termini, 2 hydrophobic transmembrane regions, and a large extracellular loop, which has many cysteine residues with conserved spacing. The member encoded by this gene may play a role in neurotransmission. In addition, a heteromeric association between this member and acid-sensing (proton-gated) ion channel 3 has been observed to co-assemble into proton-gated channels sensitive to gadolinium. Alternative splicing has been observed at this locus and two variants, encoding distinct isoforms, have been identified. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3190605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASIC2	NM_183377.2	c.1145C>T	p.Ala382Val	missense_variant	5/10	ENST00000225823.7	NP_899233.1
ASIC2	NM_001094.5	c.992C>T	p.Ala331Val	missense_variant	5/10		NP_001085.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASIC2	ENST00000225823.7	c.1145C>T	p.Ala382Val	missense_variant	5/10	1	NM_183377.2	ENSP00000225823
ASIC2	ENST00000359872.6	c.992C>T	p.Ala331Val	missense_variant	5/10	1		ENSP00000352934	P1
ASIC2	ENST00000448983.1	n.550C>T		non_coding_transcript_exon_variant	6/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461326 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726954

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2023

The c.1145C>T (p.A382V) alteration is located in exon 5 (coding exon 5) of the ASIC2 gene. This alteration results from a C to T substitution at nucleotide position 1145, causing the alanine (A) at amino acid position 382 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.3	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.25
Sift	Benign	0.093	T;T
Sift4G	Uncertain	0.032	D;D
Polyphen		1.0	.;D
Vest4		0.39
MutPred		0.65		.;Loss of disorder (P = 0.0881);
MVP		0.27
MPC		1.0
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.78
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-31352994;