1-40784121-G-T

Variant names:

• chr1-40784121-G-T
• rs1170668900
• NM_004700.4:c.28G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004700.4(KCNQ4):​c.28G>T​(p.Gly10Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 146,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G10S) has been classified as Uncertain significance. The gene KCNQ4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.343
• 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

Specifications for KCNQ4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32429293).

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.28G>T	p.Gly10Cys	missense	Exon 1 of 14	NP_004691.2
	KCNQ4	NM_172163.3		c.28G>T	p.Gly10Cys	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.28G>T	p.Gly10Cys	missense	Exon 1 of 14	ENSP00000262916.6	P56696-1
	KCNQ4	ENST00000967337.1		c.28G>T	p.Gly10Cys	missense	Exon 1 of 14	ENSP00000637396.1
	KCNQ4	ENST00000967338.1		c.28G>T	p.Gly10Cys	missense	Exon 1 of 14	ENSP00000637397.1

Frequencies

GnomAD3 genomes AF: 0.00000684 AC: 1 AN: 146144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 712246 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 339706

African (AFR) AF: 0.00 AC: 0 AN: 13380

American (AMR) AF: 0.00 AC: 0 AN: 2490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5110

East Asian (EAS) AF: 0.00 AC: 0 AN: 4300

South Asian (SAS) AF: 0.00 AC: 0 AN: 16826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1536

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 641570

Other (OTH) AF: 0.00 AC: 0 AN: 23836

GnomAD4 genome AF: 0.00000684 AC: 1 AN: 146144 Hom.: 0 Cov.: 32 AF XY: 0.0000141 AC XY: 1 AN XY: 71062

African (AFR) AF: 0.00 AC: 0 AN: 40688

American (AMR) AF: 0.00 AC: 0 AN: 14746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.00 AC: 0 AN: 4950

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65830

Other (OTH) AF: 0.00 AC: 0 AN: 2008

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.9	L
PhyloP100		-0.34
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.81	P
Vest4		0.21
MutPred		0.21		Gain of sheet (P = 0.0266)
MVP		0.71
MPC		1.2
ClinPred		0.74	D
GERP RS		-1.7
PromoterAI		-0.13	Neutral
Varity_R		0.26
gMVP		0.52
Mutation Taster		=61/39	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: rs1170668900; hg19: chr1-41249793;