6-72622204-C-G

Position:

• chr6-72622204-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_019842.4(KCNQ5):​c.15C>G​(p.His5Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000093 in 1,075,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: KCNQ5 NM_019842.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.97

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]

KCNQ5 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNQ5. . Gene score misZ 3.3177 (greater than the threshold 3.09). Trascript score misZ 3.1292 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant non-syndromic intellectual disability, intellectual disability, autosomal dominant 46.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30664268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ5	NM_019842.4	c.15C>G	p.His5Gln	missense_variant	1/14	ENST00000370398.6	NP_062816.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ5	ENST00000370398.6	c.15C>G	p.His5Gln	missense_variant	1/14	1	NM_019842.4	ENSP00000359425.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.30e-7 AC: 1 AN: 1075340 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 507884

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: 0.0000498

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Nov 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.27	.;.;.;T;.;T;.;T;.;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.73	T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.4	L;L;.;.;.;.;.;L;L;L
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.5	N;.;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;.;D;D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Polyphen		0.80, 0.51, 0.87	.;.;.;.;.;.;.;P;P;P
Vest4		0.32
MutPred		0.20		Gain of solvent accessibility (P = 0.0837);Gain of solvent accessibility (P = 0.0837);Gain of solvent accessibility (P = 0.0837);Gain of solvent accessibility (P = 0.0837);Gain of solvent accessibility (P = 0.0837);Gain of solvent accessibility (P = 0.0837);Gain of solvent accessibility (P = 0.0837);Gain of solvent accessibility (P = 0.0837);Gain of solvent accessibility (P = 0.0837);Gain of solvent accessibility (P = 0.0837);
MVP		0.48
MPC		2.0
ClinPred		0.95	D
GERP RS		3.9
Varity_R		0.57
gMVP		0.34

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: rs2098915503; hg19: chr6-73331932;