Genetic Variant ASIC1:p.Met295Lys (chr12-50078467-T-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001095.4(ASIC1):c.884T>A(p.Met295Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M295T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ASIC1
NM_001095.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.35

Publications

1 publications found

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]

ASIC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21808425).

BS2

High AC in GnomAdExome4 at 20 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001095.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ASIC1	NM_001095.4	MANE Select	c.884T>A	p.Met295Lys	missense	Exon 6 of 12	NP_001086.2
ASIC1	NM_020039.4		c.884T>A	p.Met295Lys	missense	Exon 6 of 12	NP_064423.2
ASIC1	NM_001256830.2		c.986T>A	p.Met329Lys	missense	Exon 4 of 10	NP_001243759.1	P78348-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ASIC1	ENST00000447966.7	TSL:1 MANE Select	c.884T>A	p.Met295Lys	missense	Exon 6 of 12	ENSP00000400228.3	P78348-2
ASIC1	ENST00000228468.8	TSL:1	c.884T>A	p.Met295Lys	missense	Exon 6 of 12	ENSP00000228468.4	P78348-1
ASIC1	ENST00000552438.5	TSL:1	c.986T>A	p.Met329Lys	missense	Exon 4 of 10	ENSP00000450247.1	P78348-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251446

AF XY:

0.00000736

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1111984

Other (OTH)

AF:

0.0000166

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.41

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.094

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.63

M_CAP

Benign

0.023

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.5

PhyloP100

2.4

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.35

Sift

Benign

0.78

Sift4G

Benign

0.95

Polyphen

0.015

Vest4

0.37

MutPred

0.48

Gain of solvent accessibility (P = 0.0038)

MVP

0.85

MPC

1.1

ClinPred

0.11

GERP RS

3.1

Varity_R

0.30

gMVP

0.86

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over