chr17-33028338-C-G

Variant names:

• chr17-33028338-C-G
• rs757867324
• NM_183377.2:c.1042G>C

Variant summary

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

The NM_183377.2(ASIC2):​c.1042G>C​(p.Asp348His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ASIC2 NM_183377.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASIC2	NM_183377.2	c.1042G>C	p.Asp348His	missense_variant	Exon 4 of 10	ENST00000225823.7	NP_899233.1
ASIC2	NM_001094.5	c.889G>C	p.Asp297His	missense_variant	Exon 4 of 10		NP_001085.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASIC2	ENST00000225823.7	c.1042G>C	p.Asp348His	missense_variant	Exon 4 of 10	1	NM_183377.2	ENSP00000225823.2
ASIC2	ENST00000359872.6	c.889G>C	p.Asp297His	missense_variant	Exon 4 of 10	1		ENSP00000352934.6
ASIC2	ENST00000448983.1	n.447G>C		non_coding_transcript_exon_variant	Exon 5 of 7	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251448 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461834 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Uncertain	-0.043	T
MutationAssessor	Uncertain	2.1	.;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		1.0	.;D
Vest4		0.49
MutPred		0.45		.;Loss of sheet (P = 0.1158);
MVP		0.61
MPC		1.2
ClinPred		0.91	D
GERP RS		5.6
Varity_R		0.70
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs757867324; hg19: chr17-31355356; COSMIC: COSV56765303;