17-33014006-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_183377.2(ASIC2):c.1651C>G(p.Leu551Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASIC2 NM_183377.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1684474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASIC2	NM_183377.2	c.1651C>G	p.Leu551Val	missense_variant	10/10	ENST00000225823.7
ASIC2	NM_001094.5	c.1498C>G	p.Leu500Val	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASIC2	ENST00000225823.7	c.1651C>G	p.Leu551Val	missense_variant	10/10	1	NM_183377.2
ASIC2	ENST00000359872.6	c.1498C>G	p.Leu500Val	missense_variant	10/10	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Dec 13, 2021

The c.1651C>G (p.L551V) alteration is located in exon 10 (coding exon 10) of the ASIC2 gene. This alteration results from a C to G substitution at nucleotide position 1651, causing the leucine (L) at amino acid position 551 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	0.11
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	22
Dann	Benign	0.96
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.49	N;N
REVEL	Benign	0.057
Sift	Benign	0.56	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.76	.;P
Vest4		0.27
MutPred		0.22		.;Loss of stability (P = 0.1751);
MVP		0.36
MPC		0.42
ClinPred		0.50	D
GERP RS		5.0
Varity_R		0.15
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-31341024;