rs876657839

Positions:

• chr1-40838392-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000347132.10(KCNQ4):​c.1957G>A​(p.Gly653Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G653V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ4 ENST00000347132.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.42

Genes affected

KCNQ4 (HGNC:6298): (potassium voltage-gated channel subfamily Q member 4) The protein encoded by this gene forms a potassium channel that is thought to play a critical role in the regulation of neuronal excitability, particularly in sensory cells of the cochlea. The current generated by this channel is inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. The encoded protein can form a homomultimeric potassium channel or possibly a heteromultimeric channel in association with the protein encoded by the KCNQ3 gene. Defects in this gene are a cause of nonsyndromic sensorineural deafness type 2 (DFNA2), an autosomal dominant form of progressive hearing loss. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20334852).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ4	NM_004700.4	c.1957G>A	p.Gly653Ser	missense_variant	14/14	ENST00000347132.10	NP_004691.2
KCNQ4	NM_172163.3	c.1795G>A	p.Gly599Ser	missense_variant	13/13		NP_751895.1
KCNQ4	XM_017002792.2	c.940G>A	p.Gly314Ser	missense_variant	11/11		XP_016858281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10	c.1957G>A	p.Gly653Ser	missense_variant	14/14	1	NM_004700.4	ENSP00000262916	P2
KCNQ4	ENST00000509682.6	c.1795G>A	p.Gly599Ser	missense_variant	13/13	5		ENSP00000423756	A1
KCNQ4	ENST00000443478.3	c.1540G>A	p.Gly514Ser	missense_variant	13/13	5		ENSP00000406735
KCNQ4	ENST00000506017.1	n.1276G>A		non_coding_transcript_exon_variant	11/11	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 27, 2016

The p.Gly653Ser variant in KCNQ4 has not been previously reported in individuals with hearing loss and is absent from large population studies. Computational pr ediction tools and conservation analysis suggest that the p.Gly653Ser variant ma y not impact the protein, though this information is not predictive enough to ru le out pathogenicity. In summary, the clinical significance of the p.Gly653Ser v ariant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.20	T;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	.;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	-0.34	N;N;.
MutationTaster	Benign	0.73	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.96	.;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.079	.;T;T
Sift4G	Benign	0.33	.;T;T
Polyphen		0.027	B;B;B
Vest4		0.12, 0.34
MutPred		0.39		Gain of disorder (P = 0.0811);Gain of disorder (P = 0.0811);.;
MVP		0.71
MPC		1.0
ClinPred		0.54	D
GERP RS		4.9
Varity_R		0.054
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs876657839; hg19: chr1-41304064;