20-2579132-G-C

Position:

• chr20-2579132-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_080751.3(TMC2):​c.646-14G>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.685 in 1,450,072 control chromosomes in the GnomAD database, including 342,628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38433 hom., cov: 32)
  • Exomes 𝑓: 0.68 (304195 hom.)
• Consequence: TMC2 NM_080751.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0160

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 20-2579132-G-C is Benign according to our data. Variant chr20-2579132-G-C is described in ClinVar as [Benign]. Clinvar id is 1286330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC2	NM_080751.3	c.646-14G>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000358864.2
TMC2	XM_005260660.5	c.721-14G>C		splice_polypyrimidine_tract_variant, intron_variant
TMC2	XR_001754152.2	n.855-14G>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC2	ENST00000358864.2	c.646-14G>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_080751.3	P1
TMC2	ENST00000644205.1	n.805-14G>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.708 AC: 107581 AN: 151938 Hom.: 38384 Cov.: 32

Gnomad AFR AF: 0.780

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.673

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.525

Gnomad SAS AF: 0.712

Gnomad FIN AF: 0.773

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.683

GnomAD3 exomes AF: 0.689 AC: 171676 AN: 249006 Hom.: 59747 AF XY: 0.688 AC XY: 92657 AN XY: 134722

Gnomad AFR exome AF: 0.784

Gnomad AMR exome AF: 0.724

Gnomad ASJ exome AF: 0.620

Gnomad EAS exome AF: 0.506

Gnomad SAS exome AF: 0.709

Gnomad FIN exome AF: 0.760

Gnomad NFE exome AF: 0.684

Gnomad OTH exome AF: 0.670

GnomAD4 exome AF: 0.682 AC: 885689 AN: 1298016 Hom.: 304195 Cov.: 18 AF XY: 0.683 AC XY: 446788 AN XY: 654602

Gnomad4 AFR exome AF: 0.785

Gnomad4 AMR exome AF: 0.719

Gnomad4 ASJ exome AF: 0.613

Gnomad4 EAS exome AF: 0.501

Gnomad4 SAS exome AF: 0.705

Gnomad4 FIN exome AF: 0.752

Gnomad4 NFE exome AF: 0.681

Gnomad4 OTH exome AF: 0.681

GnomAD4 genome AF: 0.708 AC: 107682 AN: 152056 Hom.: 38433 Cov.: 32 AF XY: 0.709 AC XY: 52734 AN XY: 74328

Gnomad4 AFR AF: 0.780

Gnomad4 AMR AF: 0.673

Gnomad4 ASJ AF: 0.601

Gnomad4 EAS AF: 0.525

Gnomad4 SAS AF: 0.711

Gnomad4 FIN AF: 0.773

Gnomad4 NFE AF: 0.684

Gnomad4 OTH AF: 0.682

Alfa AF: 0.629 Hom.: 3619

Bravo AF: 0.705

Asia WGS AF: 0.655 AC: 2280 AN: 3478

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	clinical testing	GeneDx	Jun 19, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	9.5
DANN	Benign	0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs6083735; hg19: chr20-2559778; COSMIC: COSV62650970;