1-40784121-G-A

Variant names:

• chr1-40784121-G-A
• rs1170668900
• NM_004700.4:c.28G>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.28G>A​(p.Gly10Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000562 in 712,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• 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

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=0.17419994).

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>A	p.Gly10Ser	missense	Exon 1 of 14	NP_004691.2
	KCNQ4	NM_172163.3		c.28G>A	p.Gly10Ser	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>A	p.Gly10Ser	missense	Exon 1 of 14	ENSP00000262916.6	P56696-1
	KCNQ4	ENST00000967337.1		c.28G>A	p.Gly10Ser	missense	Exon 1 of 14	ENSP00000637396.1
	KCNQ4	ENST00000967338.1		c.28G>A	p.Gly10Ser	missense	Exon 1 of 14	ENSP00000637397.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000562 AC: 4 AN: 712244 Hom.: 0 Cov.: 9 AF XY: 0.00000589 AC XY: 2 AN XY: 339704

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: 0.000233 AC: 1 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: 0.00000312 AC: 2 AN: 641568

Other (OTH) AF: 0.0000420 AC: 1 AN: 23836

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal dominant nonsyndromic hearing loss 2A (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	0.060	D
MutationAssessor	Benign	1.9	L
PhyloP100		-0.34
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.27	N
REVEL	Uncertain	0.41
Sift	Benign	0.11	T
Sift4G	Benign	0.16	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.097		Gain of phosphorylation at G10 (P = 0.0037)
MVP		0.65
MPC		1.1
ClinPred		0.10	T
GERP RS		-1.7
PromoterAI		-0.11	Neutral
Varity_R		0.068
gMVP		0.47
Mutation Taster		=77/23	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;