12-50059893-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001095.4(ASIC1):​c.497G>A​(p.Arg166Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

ASIC1
NM_001095.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.59
Variant links:
Genes affected
ASIC1 (HGNC:100): (acid sensing ion channel subunit 1) This gene encodes a member of the acid-sensing ion channel (ASIC) family of proteins, which are part of the degenerin/epithelial sodium channel (DEG/ENaC) superfamily. Members of the ASIC family are sensitive to amiloride and function in neurotransmission. The encoded proteins function in learning, pain transduction, touch sensation, and development of memory and fear. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.08268812).
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ASIC1NM_001095.4 linkuse as main transcriptc.497G>A p.Arg166Gln missense_variant 3/12 ENST00000447966.7 NP_001086.2 P78348-2A8K1U5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ASIC1ENST00000447966.7 linkuse as main transcriptc.497G>A p.Arg166Gln missense_variant 3/121 NM_001095.4 ENSP00000400228.3 P78348-2
ASIC1ENST00000228468.8 linkuse as main transcriptc.497G>A p.Arg166Gln missense_variant 3/121 ENSP00000228468.4 P78348-1
ASIC1ENST00000453327.7 linkuse as main transcriptc.5G>A p.Arg2Gln missense_variant 1/112 ENSP00000402896.3 H7C1W9
ASIC1ENST00000550558.5 linkuse as main transcriptn.497G>A non_coding_transcript_exon_variant 3/132 ENSP00000448263.1 F8VSK4

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152146
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00329
Gnomad AMR
AF:
0.0000654
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
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251300
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135872
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461844
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152146
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
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:
0.0000495
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 05, 2023The c.497G>A (p.R166Q) alteration is located in exon 3 (coding exon 2) of the ASIC1 gene. This alteration results from a G to A substitution at nucleotide position 497, causing the arginine (R) at amino acid position 166 to be replaced by a glutamine (Q). 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
0.077
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.43
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
.;T
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.14
FATHMM_MKL
Benign
0.55
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.083
T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
1.6
L;L
PrimateAI
Benign
0.41
T
PROVEAN
Benign
0.060
N;N
REVEL
Benign
0.071
Sift
Benign
0.082
T;T
Sift4G
Benign
0.11
T;T
Polyphen
0.0020
B;B
Vest4
0.33
MutPred
0.50
Gain of catalytic residue at R166 (P = 0.0763);Gain of catalytic residue at R166 (P = 0.0763);
MVP
0.41
MPC
0.85
ClinPred
0.22
T
GERP RS
4.1
Varity_R
0.12
gMVP
0.50

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

LitVar

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

Other links and lift over

dbSNP: rs773864447; hg19: chr12-50453676; API