NM_004700.4:c.80C>G

Variant names:

• chr1-40784173-C-G
• rs1001249688
• NM_004700.4:c.80C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_004700.4(KCNQ4):​c.80C>G​(p.Thr27Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,116,506 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T27T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0820
• 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
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2784923).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004700.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ4	NM_004700.4	MANE Select	c.80C>G	p.Thr27Arg	missense	Exon 1 of 14	NP_004691.2
	KCNQ4	NM_172163.3		c.80C>G	p.Thr27Arg	missense	Exon 1 of 13	NP_751895.1	P56696-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ4	ENST00000347132.10	TSL:1 MANE Select	c.80C>G	p.Thr27Arg	missense	Exon 1 of 14	ENSP00000262916.6	P56696-1
	KCNQ4	ENST00000967337.1		c.80C>G	p.Thr27Arg	missense	Exon 1 of 14	ENSP00000637396.1
	KCNQ4	ENST00000967338.1		c.80C>G	p.Thr27Arg	missense	Exon 1 of 14	ENSP00000637397.1

Frequencies

GnomAD3 genomes AF: 0.000102 AC: 15 AN: 147112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000343

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000151

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 10 AN: 969284 Hom.: 0 Cov.: 19 AF XY: 0.00000854 AC XY: 4 AN XY: 468144

African (AFR) AF: 0.000383 AC: 7 AN: 18290

American (AMR) AF: 0.00 AC: 0 AN: 8792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10800

East Asian (EAS) AF: 0.00 AC: 0 AN: 9158

South Asian (SAS) AF: 0.00 AC: 0 AN: 31844

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2292

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 842320

Other (OTH) AF: 0.00 AC: 0 AN: 34534

GnomAD4 genome AF: 0.000109 AC: 16 AN: 147222 Hom.: 0 Cov.: 32 AF XY: 0.000112 AC XY: 8 AN XY: 71724

African (AFR) AF: 0.000367 AC: 15 AN: 40894

American (AMR) AF: 0.00 AC: 0 AN: 14874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3400

East Asian (EAS) AF: 0.00 AC: 0 AN: 4988

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66122

Other (OTH) AF: 0.00 AC: 0 AN: 2058

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000982

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.3	L
PhyloP100		0.082
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.87	N
REVEL	Uncertain	0.36
Sift	Benign	0.089	T
Sift4G	Benign	0.34	T
Polyphen		0.98	D
Vest4		0.15
MutPred		0.22		Loss of glycosylation at T27 (P = 0.0323)
MVP		0.77
MPC		1.6
ClinPred		0.41	T
GERP RS		0.46
PromoterAI		0.082	Neutral
Varity_R		0.13
gMVP		0.63
Mutation Taster		=72/28	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: rs1001249688; hg19: chr1-41249845;