chr6-72622211-G-A

Position:

chr6-72622211-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_019842.4(KCNQ5):c.22G>A(p.Gly8Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00188 in 1,230,340 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 2 hom. )

Consequence

KCNQ5
NM_019842.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.57

Variant links:

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 links:

KCNQ5 (HGNC:):

KCNQ5 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNQ5. . Gene score misZ 3.3177 (greater than the threshold 3.09). Trascript score misZ 3.1292 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant non-syndromic intellectual disability, intellectual disability, autosomal dominant 46.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024060905).

BP6

Variant 6-72622211-G-A is Benign according to our data. Variant chr6-72622211-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 975566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00138 (210/152094) while in subpopulation AMR AF= 0.00236 (36/15286). AF 95% confidence interval is 0.00199. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 210 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ5	NM_019842.4 linkuse as main transcript	c.22G>A	p.Gly8Arg	missense_variant	1/14	ENST00000370398.6	NP_062816.2	Q9NR82-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ5	ENST00000370398.6 linkuse as main transcript	c.22G>A	p.Gly8Arg	missense_variant	1/14	1	NM_019842.4	ENSP00000359425.1		Q9NR82-1

Frequencies

GnomAD3 genomes

AF:

0.00138

AC:

210

AN:

151986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00228

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00186

AC:

AN:

538

Hom.:

AF XY:

0.00316

AC XY:

AN XY:

316

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00216

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00195

AC:

2103

AN:

1078246

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

1003

AN XY:

509440

show subpopulations

Gnomad4 AFR exome

AF:

0.0000886

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.000142

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000328

Gnomad4 NFE exome

AF:

0.00218

Gnomad4 OTH exome

AF:

0.00182

GnomAD4 genome

AF:

0.00138

AC:

210

AN:

152094

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00236

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00228

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00196

Hom.:

Bravo

AF:

0.00146

ExAC

AF:

0.000207

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	KCNQ5: PP2, PP3, BS1 -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

KCNQ5-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Intellectual disability

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

.;.;.;T;.;T;.;T;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.026

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.90

D;D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0024

T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.10

MutationAssessor

Benign

0.90

L;L;.;.;.;.;.;L;L;L

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.54

N;.;N;N;N;N;N;N;N;.

REVEL

Uncertain

0.38

Sift

Uncertain

0.0050

D;.;D;D;D;D;D;D;D;.

Sift4G

Uncertain

0.021

D;D;D;D;D;D;D;D;T;D

Polyphen

0.028, 0.0050, 0.047

.;.;.;.;.;.;.;B;B;B

Vest4

0.24

MutPred

0.20

Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);

MVP

0.12

MPC

3.1

ClinPred

0.23

GERP RS

3.9

Varity_R

0.28

gMVP

0.19

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over