dbSNP rs1554210415: KCNQ5:p.Gly347Ser (chr6-73111317-G-A) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_019842.4(KCNQ5):c.1039G>A(p.Gly347Ser) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G347A) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

KCNQ5
NM_019842.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 9.91

Publications

1 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: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-73111318-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 975567.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

PP5

Variant 6-73111317-G-A is Pathogenic according to our data. Variant chr6-73111317-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 521883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNQ5	NM_019842.4	MANE Select	c.1039G>A	p.Gly347Ser	missense	Exon 7 of 14	NP_062816.2
KCNQ5	NM_001160133.2		c.1039G>A	p.Gly347Ser	missense	Exon 7 of 15	NP_001153605.1	Q9NR82-6
KCNQ5	NM_001160132.2		c.1039G>A	p.Gly347Ser	missense	Exon 7 of 14	NP_001153604.1	Q9NR82-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNQ5	ENST00000370398.6	TSL:1 MANE Select	c.1039G>A	p.Gly347Ser	missense	Exon 7 of 14	ENSP00000359425.1	Q9NR82-1
KCNQ5	ENST00000629977.2	TSL:1	c.1039G>A	p.Gly347Ser	missense	Exon 7 of 13	ENSP00000485743.1	Q9NR82-2
KCNQ5	ENST00000370392.5	TSL:1	c.1039G>A	p.Gly347Ser	missense	Exon 7 of 9	ENSP00000359419.1	Q9NR82-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Global developmental delay (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.87

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

PhyloP100

9.9

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.024

Polyphen

1.0

Vest4

0.82

MutPred

0.68

Gain of catalytic residue at G347 (P = 0.0811)

MVP

0.98

MPC

2.8

ClinPred

1.0

GERP RS

5.1

Varity_R

0.95

gMVP

0.98

Mutation Taster

=26/74

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over