rs1135401955

Variant names:

• chr6-73003943-T-G
• rs1135401955
• NM_019842.4:c.434T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_019842.4(KCNQ5):​c.434T>G​(p.Val145Gly) 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)
• Consequence: KCNQ5 NM_019842.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.91
• Publications: 4 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 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792
• PP5: Variant 6-73003943-T-G is Pathogenic according to our data. Variant chr6-73003943-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 431385.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	c.434T>G	p.Val145Gly	missense_variant	Exon 2 of 14	ENST00000370398.6	NP_062816.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ5	ENST00000370398.6	c.434T>G	p.Val145Gly	missense_variant	Exon 2 of 14	1	NM_019842.4	ENSP00000359425.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

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	0.98
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	.;.;.;D;.;D;.;D;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L;L;.;.;.;.;.;L;L;L
PhyloP100		5.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.3	D;.;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;.;D;D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;.;.;D;D;D
Vest4		0.63
MutPred		0.58		Loss of stability (P = 0.0102);Loss of stability (P = 0.0102);Loss of stability (P = 0.0102);Loss of stability (P = 0.0102);Loss of stability (P = 0.0102);Loss of stability (P = 0.0102);Loss of stability (P = 0.0102);Loss of stability (P = 0.0102);Loss of stability (P = 0.0102);Loss of stability (P = 0.0102);
MVP		0.95
MPC		3.3
ClinPred		1.0	D
GERP RS		5.6
PromoterAI		-0.018	Neutral
Varity_R		0.95
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1135401955; hg19: chr6-73713666;