17-33014009-G-C

Variant names:

• chr17-33014009-G-C
• rs375691699
• NM_183377.2:c.1648C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_183377.2(ASIC2):​c.1648C>G​(p.Pro550Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,620 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P550S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ASIC2 NM_183377.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.53
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183377.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASIC2	NM_183377.2	MANE Select	c.1648C>G	p.Pro550Ala	missense	Exon 10 of 10	NP_899233.1	Q16515-2
	ASIC2	NM_001094.5		c.1495C>G	p.Pro499Ala	missense	Exon 10 of 10	NP_001085.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASIC2	ENST00000225823.7	TSL:1 MANE Select	c.1648C>G	p.Pro550Ala	missense	Exon 10 of 10	ENSP00000225823.2	Q16515-2
	ASIC2	ENST00000359872.6	TSL:1	c.1495C>G	p.Pro499Ala	missense	Exon 10 of 10	ENSP00000352934.6	Q16515-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452620 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 721458

African (AFR) AF: 0.00 AC: 0 AN: 33258

American (AMR) AF: 0.00 AC: 0 AN: 43762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25954

East Asian (EAS) AF: 0.00 AC: 0 AN: 39344

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107512

Other (OTH) AF: 0.00 AC: 0 AN: 60044

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.97	L
PhyloP100		9.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.39
MutPred		0.69		Gain of sheet (P = 0.0149)
MVP		0.39
MPC		0.87
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.31
gMVP		0.92

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

Other links and lift over

dbSNP: rs375691699; hg19: chr17-31341027;