1-40784200-CG-CGG

Variant names:

• chr1-40784200-C-CG
• rs1168470485
• NM_004700.4:c.110dupG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_004700.4(KCNQ4):​c.110dupG​(p.Gly38ArgfsTer198) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 147,406 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ4 NM_004700.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 1.66
• 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-40784200-C-CG is Pathogenic according to our data. Variant chr1-40784200-C-CG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3343127.

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.110dupG	p.Gly38ArgfsTer198	frameshift	Exon 1 of 14	NP_004691.2
	KCNQ4	NM_172163.3		c.110dupG	p.Gly38ArgfsTer198	frameshift	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.110dupG	p.Gly38ArgfsTer198	frameshift	Exon 1 of 14	ENSP00000262916.6	P56696-1
	KCNQ4	ENST00000967337.1		c.110dupG	p.Gly38ArgfsTer198	frameshift	Exon 1 of 14	ENSP00000637396.1
	KCNQ4	ENST00000967338.1		c.110dupG	p.Gly38ArgfsTer198	frameshift	Exon 1 of 14	ENSP00000637397.1

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 147406 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000303

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000185 AC: 18 AN: 971506 Hom.: 0 Cov.: 24 AF XY: 0.0000151 AC XY: 7 AN XY: 464262

African (AFR) AF: 0.00 AC: 0 AN: 18676

American (AMR) AF: 0.00 AC: 0 AN: 4892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9370

East Asian (EAS) AF: 0.00 AC: 0 AN: 12174

South Asian (SAS) AF: 0.00 AC: 0 AN: 21892

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2328

European-Non Finnish (NFE) AF: 0.0000199 AC: 17 AN: 853996

Other (OTH) AF: 0.0000283 AC: 1 AN: 35358

GnomAD4 genome AF: 0.0000136 AC: 2 AN: 147406 Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 1 AN XY: 71708

African (AFR) AF: 0.00 AC: 0 AN: 40880

American (AMR) AF: 0.00 AC: 0 AN: 14890

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5008

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.0000303 AC: 2 AN: 66014

Other (OTH) AF: 0.00 AC: 0 AN: 2028

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=17/183	disease causing (fs/PTC)

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: rs1168470485; hg19: chr1-41249872;