rs368870705

chr9-135702320-G-Achr9-135702320-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020822.3(KCNT1):c.62G>A(p.Gly21Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. G21V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.350

Genes affected

KCNT1 (HGNC:18865): (potassium sodium-activated channel subfamily T member 1) Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a sodium-activated potassium channel subunit which is thought to function in ion conductance and developmental signaling pathways. Mutations in this gene cause the early-onset epileptic disorders, malignant migrating partial seizures of infancy and autosomal dominant nocturnal frontal lobe epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

SOHLH1 (HGNC:27845): (spermatogenesis and oogenesis specific basic helix-loop-helix 1) This gene encodes one of testis-specific transcription factors which are essential for spermatogenesis, oogenesis and folliculogenesis. This gene is located on chromosome 9. Mutations in this gene are associated with nonobstructive azoospermia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2949471).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT1	NM_020822.3	c.62G>A	p.Gly21Asp	missense_variant	1/31	ENST00000371757.7
KCNT1	NM_001272003.2	c.62G>A	p.Gly21Asp	missense_variant	1/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7	c.62G>A	p.Gly21Asp	missense_variant	1/31	1	NM_020822.3	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 07, 2017

This sequence change replaces glycine with aspartic acid at codon 21 of the KCNT1 protein (p.Gly21Asp). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with KCNT1-related disease. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	14
Dann	Uncertain	0.98
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.53	T;T;T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.59	N;N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.46	N;.;N
REVEL	Benign	0.13
Sift	Uncertain	0.028	D;.;D
Sift4G	Uncertain	0.015	D;T;D
Vest4		0.38
MutPred		0.36		Loss of methylation at R18 (P = 0.0536);Loss of methylation at R18 (P = 0.0536);Loss of methylation at R18 (P = 0.0536);
MVP		0.18
MPC		0.82
ClinPred		0.22	T
GERP RS		2.2
gMVP		0.11

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: rs368870705; hg19: chr9-138594166;