17-33028396-C-T

Position:

• chr17-33028396-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_183377.2(ASIC2):​c.988-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 1,614,000 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (76 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (72 hom.)
• Consequence: ASIC2 NM_183377.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.008521
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.146

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 17-33028396-C-T is Benign according to our data. Variant chr17-33028396-C-T is described in ClinVar as [Benign]. Clinvar id is 791344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASIC2	NM_183377.2	c.988-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000225823.7	NP_899233.1
ASIC2	NM_001094.5	c.835-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001085.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASIC2	ENST00000225823.7	c.988-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_183377.2	ENSP00000225823
ASIC2	ENST00000359872.6	c.835-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000352934	P1
ASIC2	ENST00000448983.1	n.393-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2694 AN: 152164 Hom.: 76 Cov.: 33

Gnomad AFR AF: 0.0613

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00726

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00476 AC: 1195 AN: 251148 Hom.: 38 AF XY: 0.00363 AC XY: 493 AN XY: 135778

Gnomad AFR exome AF: 0.0649

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00173 AC: 2534 AN: 1461718 Hom.: 72 Cov.: 33 AF XY: 0.00147 AC XY: 1067 AN XY: 727152

Gnomad4 AFR exome AF: 0.0609

Gnomad4 AMR exome AF: 0.00342

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000657

Gnomad4 OTH exome AF: 0.00402

GnomAD4 genome AF: 0.0177 AC: 2696 AN: 152282 Hom.: 76 Cov.: 33 AF XY: 0.0177 AC XY: 1319 AN XY: 74464

Gnomad4 AFR AF: 0.0612

Gnomad4 AMR AF: 0.00725

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00915 Hom.: 15

Bravo AF: 0.0200

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 20, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	14
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0085
dbscSNV1_RF	Benign	0.034
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

Other links and lift over

dbSNP: rs3025242; hg19: chr17-31355414;