rs876657839

Variant names:

• chr1-40838392-G-A
• rs876657839
• NM_004700.4:c.1957G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004700.4(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. 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 NM_004700.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.42
• Publications: 0 publications found

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]

KCNQ4 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 2A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
KCNQ4	NM_004700.4	c.1957G>A	p.Gly653Ser	missense_variant	Exon 14 of 14	ENST00000347132.10	NP_004691.2
KCNQ4	NM_172163.3	c.1795G>A	p.Gly599Ser	missense_variant	Exon 13 of 13		NP_751895.1
KCNQ4	XM_017002792.2	c.940G>A	p.Gly314Ser	missense_variant	Exon 11 of 11		XP_016858281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10	c.1957G>A	p.Gly653Ser	missense_variant	Exon 14 of 14	1	NM_004700.4	ENSP00000262916.6
KCNQ4	ENST00000509682.6	c.1795G>A	p.Gly599Ser	missense_variant	Exon 13 of 13	5		ENSP00000423756.2
KCNQ4	ENST00000443478.3	c.1537G>A	p.Gly513Ser	missense_variant	Exon 13 of 13	5		ENSP00000406735.3
KCNQ4	ENST00000506017.1	n.1276G>A		non_coding_transcript_exon_variant	Exon 11 of 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

Jan 27, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.
PhyloP100		3.4
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
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs876657839; hg19: chr1-41304064;