6-73111384-C-T

Position:

• chr6-73111384-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_019842.4(KCNQ5):​c.1106C>T​(p.Pro369Leu) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P369R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ5 NM_019842.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.83

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a helix (size 15) in uniprot entity KCNQ5_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_019842.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-73111384-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 802242.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ5	NM_019842.4	c.1106C>T	p.Pro369Leu	missense_variant	7/14	ENST00000370398.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ5	ENST00000370398.6	c.1106C>T	p.Pro369Leu	missense_variant	7/14	1	NM_019842.4	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 46 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Nov 17, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	.;.;.;T;.;T;.;D;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M;.;.;.;.;.;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-9.2	D;.;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.;D;D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0, 1.0	.;.;.;.;.;.;.;D;D;D
Vest4		0.70
MutPred		0.51		Loss of glycosylation at P369 (P = 0.014);Loss of glycosylation at P369 (P = 0.014);Loss of glycosylation at P369 (P = 0.014);Loss of glycosylation at P369 (P = 0.014);Loss of glycosylation at P369 (P = 0.014);Loss of glycosylation at P369 (P = 0.014);Loss of glycosylation at P369 (P = 0.014);Loss of glycosylation at P369 (P = 0.014);Loss of glycosylation at P369 (P = 0.014);Loss of glycosylation at P369 (P = 0.014);
MVP		0.93
MPC		2.9
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.86
gMVP		0.99

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

Other links and lift over

dbSNP: rs1135401958; hg19: chr6-73821107; COSMIC: COSV59677893;