rs727505133

Variant names:

• chr1-40838389-C-G
• rs727505133
• NM_004700.4:c.1954C>G

Variant summary

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

The NM_004700.4(KCNQ4):​c.1954C>G​(p.Leu652Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.18
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ4	NM_004700.4	c.1954C>G	p.Leu652Val	missense_variant	Exon 14 of 14	ENST00000347132.10	NP_004691.2
KCNQ4	NM_172163.3	c.1792C>G	p.Leu598Val	missense_variant	Exon 13 of 13		NP_751895.1
KCNQ4	XM_017002792.2	c.937C>G	p.Leu313Val	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.1954C>G	p.Leu652Val	missense_variant	Exon 14 of 14	1	NM_004700.4	ENSP00000262916.6
KCNQ4	ENST00000509682.6	c.1792C>G	p.Leu598Val	missense_variant	Exon 13 of 13	5		ENSP00000423756.2
KCNQ4	ENST00000443478.3	c.1534C>G	p.Leu512Val	missense_variant	Exon 13 of 13	5		ENSP00000406735.3
KCNQ4	ENST00000506017.1	n.1273C>G		non_coding_transcript_exon_variant	Exon 11 of 11	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461720 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111924

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 19, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Leu652Val variant in KCNQ4 has not been reported in individuals with hearing loss or in large population studies. Computational prediction tools and conserv ation analyses do not provide strong support for or against an impact to the pro tein. In summary, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;T;.
Eigen	Benign	0.045
Eigen_PC	Benign	0.047
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	.;D;D
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.4	M;M;.
PhyloP100		2.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.9	.;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.042	.;D;D
Sift4G	Benign	0.061	.;T;T
Polyphen		1.0	D;D;P
Vest4		0.095, 0.33
MutPred		0.48		Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);.;
MVP		0.88
MPC		2.1
ClinPred		0.78	D
GERP RS		2.9
Varity_R		0.11
gMVP		0.46
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs727505133; hg19: chr1-41304061;