6-73133443-C-T

Variant names:

• chr6-73133443-C-T
• rs1554213240
• NM_019842.4:c.1270C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_019842.4(KCNQ5):​c.1270C>T​(p.Arg424*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000658 in 152,074 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R424R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: KCNQ5 NM_019842.4 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.68
• Publications: 0 publications found

Genes affected

KCNQ5 (HGNC:6299): (potassium voltage-gated channel subfamily Q member 5) This gene is a member of the KCNQ potassium channel gene family that is differentially expressed in subregions of the brain and in skeletal muscle. The protein encoded by this gene yields currents that activate slowly with depolarization and can form heteromeric channels with the protein encoded by the KCNQ3 gene. Currents expressed from this protein have voltage dependences and inhibitor sensitivities in common with M-currents. They are also inhibited by M1 muscarinic receptor activation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

KCNQ5-AS1 (HGNC:40323): (KCNQ5 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 10 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019842.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ5	NM_019842.4	MANE Select	c.1270C>T	p.Arg424*	stop_gained	Exon 10 of 14	NP_062816.2
	KCNQ5	NM_001160133.2		c.1327C>T	p.Arg443*	stop_gained	Exon 11 of 15	NP_001153605.1
	KCNQ5	NM_001160132.2		c.1300C>T	p.Arg434*	stop_gained	Exon 10 of 14	NP_001153604.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ5	ENST00000370398.6	TSL:1 MANE Select	c.1270C>T	p.Arg424*	stop_gained	Exon 10 of 14	ENSP00000359425.1
	KCNQ5	ENST00000629977.2	TSL:1	c.1243C>T	p.Arg415*	stop_gained	Exon 9 of 13	ENSP00000485743.1
	KCNQ5	ENST00000342056.6	TSL:5	c.1327C>T	p.Arg443*	stop_gained	Exon 11 of 15	ENSP00000345055.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 33

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74264

African (AFR) AF: 0.00 AC: 0 AN: 41390

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2086

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1327C>T (p.R443*) alteration, located in coding exon 11 of the KCNQ5 gene, consists of a C to T substitution at nucleotide position 1327. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 443. This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of KCNQ5 has not been clearly established as a mechanism of disease. Based on data from the Genome Aggregation Database (gnomAD), the KCNQ5 c.1327C>T alteration was not observed, with coverage at this position. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		4.7
Vest4		0.97
ClinPred		1.0	D
GERP RS		5.6
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs1554213240; hg19: chr6-73843166; COSMIC: COSV100573305; COSMIC: COSV100573305;