17-33111919-G-C

Position:

chr17-33111919-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_183377.2(ASIC2):c.857C>G(p.Thr286Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,611,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

ASIC2
NM_183377.2 missense, splice_region

Scores

Splicing: ADA: 0.1018

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.99

Variant links:

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]

ASIC2 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.767

BS2

High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASIC2	NM_183377.2 linkuse as main transcript	c.857C>G	p.Thr286Arg	missense_variant, splice_region_variant	2/10	ENST00000225823.7	NP_899233.1
ASIC2	NM_001094.5 linkuse as main transcript	c.704C>G	p.Thr235Arg	missense_variant, splice_region_variant	2/10		NP_001085.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASIC2	ENST00000225823.7 linkuse as main transcript	c.857C>G	p.Thr286Arg	missense_variant, splice_region_variant	2/10	1	NM_183377.2	ENSP00000225823		Q16515-2
	ENST00000584688.1 linkuse as main transcript	n.62G>C		non_coding_transcript_exon_variant	1/3	4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000807

AC:

AN:

247978

Hom.:

AF XY:

0.00000747

AC XY:

AN XY:

133932

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1458988

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

725674

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

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:

0.0000243

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

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 submitter

clinical testing

Ambry Genetics

Oct 29, 2021

The c.857C>G (p.T286R) alteration is located in exon 2 (coding exon 2) of the ASIC2 gene. This alteration results from a C to G substitution at nucleotide position 857, causing the threonine (T) at amino acid position 286 to be replaced by an arginine (R). 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

Uncertain

0.35

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

.;T

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.85

T;T

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Uncertain

0.024

MutationAssessor

Pathogenic

3.0

.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Uncertain

0.54

Sift

Uncertain

0.011

D;D

Sift4G

Benign

0.064

T;T

Polyphen

0.97

.;D

Vest4

0.76

MVP

0.58

MPC

1.0

ClinPred

0.99

GERP RS

5.1

Varity_R

0.75

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.10

dbscSNV1_RF

Benign

0.41

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.

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