20-2594723-G-T

Variant names:

• chr20-2594723-G-T
• rs6050469
• NM_080751.3:c.934-102G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_080751.3(TMC2):​c.934-102G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000176 in 1,135,176 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.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: TMC2 NM_080751.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26
• Publications: 0 publications found

Genes affected

TMC2 (HGNC:16527): (transmembrane channel like 2) This gene encodes a transmembrane protein that is necesssary for mechanotransduction in cochlear hair cells of the inner ear. Mutations in this gene may underlie hereditary disorders of balance and hearing. [provided by RefSeq, Aug 2015]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC2	NM_080751.3	c.934-102G>T		intron_variant	Intron 8 of 19	ENST00000358864.2	NP_542789.2
TMC2	XM_005260660.5	c.1009-102G>T		intron_variant	Intron 6 of 17		XP_005260717.1
TMC2	XR_001754152.2	n.1143-102G>T		intron_variant	Intron 6 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC2	ENST00000358864.2	c.934-102G>T		intron_variant	Intron 8 of 19	1	NM_080751.3	ENSP00000351732.1
TMC2	ENST00000644205.1	n.1093-102G>T		intron_variant	Intron 6 of 14

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000176 AC: 2 AN: 1135176 Hom.: 0 AF XY: 0.00000352 AC XY: 2 AN XY: 567444

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26102

American (AMR) AF: 0.00 AC: 0 AN: 31264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19114

East Asian (EAS) AF: 0.00 AC: 0 AN: 37396

South Asian (SAS) AF: 0.0000152 AC: 1 AN: 65582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4570

European-Non Finnish (NFE) AF: 0.00000117 AC: 1 AN: 853388

Other (OTH) AF: 0.00 AC: 0 AN: 48604

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.17
DANN	Benign	0.49
PhyloP100		-1.3

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

Other links and lift over

dbSNP: rs6050469; hg19: chr20-2575369;