6-72622191-T-C

Position:

• chr6-72622191-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_019842.4(KCNQ5):​c.2T>C​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ5 NM_019842.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.99

Genes affected

KCNQ5 (HGNC:6299): (potassium voltage-gated channel subfamily Q member 5) This gene is a member of the KCNQ potassium channel gene family that is differentially expressed in subregions of the brain and in skeletal muscle. The protein encoded by this gene yields currents that activate slowly with depolarization and can form heteromeric channels with the protein encoded by the KCNQ3 gene. Currents expressed from this protein have voltage dependences and inhibitor sensitivities in common with M-currents. They are also inhibited by M1 muscarinic receptor activation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-72622191-T-C is Pathogenic according to our data. Variant chr6-72622191-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2854702.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ5	NM_019842.4	c.2T>C	p.Met1?	start_lost	1/14	ENST00000370398.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ5	ENST00000370398.6	c.2T>C	p.Met1?	start_lost	1/14	1	NM_019842.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1071660 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 506074

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 20, 2023

Disruption of the initiator codon has been observed in individual(s) with clinical features of KCNQ5-related conditions (Invitae). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the KCNQ5 mRNA. The next in-frame methionine is located at codon 36. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.28	.;.;.;T;.;T;.;T;.;.
Eigen	Benign	-0.067
Eigen_PC	Benign	0.038
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PROVEAN	Benign	-1.6	N;.;N;N;N;N;N;N;N;.
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;.;D;D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Polyphen		0.089, 0.19, 0.14	.;.;.;.;.;.;.;B;B;B
Vest4		0.64
MutPred		0.91		Gain of phosphorylation at M1 (P = 4e-04);Gain of phosphorylation at M1 (P = 4e-04);Gain of phosphorylation at M1 (P = 4e-04);Gain of phosphorylation at M1 (P = 4e-04);Gain of phosphorylation at M1 (P = 4e-04);Gain of phosphorylation at M1 (P = 4e-04);Gain of phosphorylation at M1 (P = 4e-04);Gain of phosphorylation at M1 (P = 4e-04);Gain of phosphorylation at M1 (P = 4e-04);Gain of phosphorylation at M1 (P = 4e-04);
MVP		0.64
ClinPred		0.97	D
GERP RS		3.9
Varity_R		0.96
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-73331919;