Genetic Variant NM_019842.4:c.1021C>A (chr6-73105359-C-A) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_019842.4(KCNQ5):c.1021C>A(p.Leu341Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNQ5
NM_019842.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.06

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

intellectual disability, autosomal dominant 46
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KCNQ5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_019842.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.897

PP5

Variant 6-73105359-C-A is Pathogenic according to our data. Variant chr6-73105359-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 431386.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ5	NM_019842.4 link	c.1021C>A	p.Leu341Ile	missense_variant	Exon 6 of 14	ENST00000370398.6	NP_062816.2	Q9NR82-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ5	ENST00000370398.6 link	c.1021C>A	p.Leu341Ile	missense_variant	Exon 6 of 14	1	NM_019842.4	ENSP00000359425.1		Q9NR82-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1451946

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722534

African (AFR)

AF:

0.00

AC:

AN:

33212

American (AMR)

AF:

0.00

AC:

AN:

44144

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25970

East Asian (EAS)

AF:

0.00

AC:

AN:

39564

South Asian (SAS)

AF:

0.00

AC:

AN:

84942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104948

Other (OTH)

AF:

0.00

AC:

AN:

60090

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 46

Pathogenic:1

Apr 26, 2022

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

.;.;.;T;.;T;.;D;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.90

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

2.0

M;M;.;.;.;.;.;M;M;M

PhyloP100

4.1

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.9

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

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0050

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

Polyphen

1.0, 0.96, 1.0

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

Vest4

0.79

MutPred

0.82

Gain of catalytic residue at L346 (P = 0.1158);Gain of catalytic residue at L346 (P = 0.1158);Gain of catalytic residue at L346 (P = 0.1158);Gain of catalytic residue at L346 (P = 0.1158);Gain of catalytic residue at L346 (P = 0.1158);Gain of catalytic residue at L346 (P = 0.1158);Gain of catalytic residue at L346 (P = 0.1158);Gain of catalytic residue at L346 (P = 0.1158);Gain of catalytic residue at L346 (P = 0.1158);Gain of catalytic residue at L346 (P = 0.1158);

MVP

0.63

MPC

3.0

ClinPred

0.94

GERP RS

5.8

Varity_R

0.77

gMVP

0.94

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over