9-135702288-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020822.3(KCNT1):c.30G>A(p.Pro10=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00786 in 1,608,588 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P10P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0052 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (82 hom.)
• Consequence: KCNT1 NM_020822.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.43

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 9-135702288-G-A is Benign according to our data. Variant chr9-135702288-G-A is described in ClinVar as [Benign]. Clinvar id is 193440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135702288-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.43 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00522 (795/152156) while in subpopulation SAS AF= 0.0162 (78/4824). AF 95% confidence interval is 0.0133. There are 5 homozygotes in gnomad4. There are 395 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 797 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNT1	NM_020822.3	c.30G>A	p.Pro10=	synonymous_variant	1/31	ENST00000371757.7
KCNT1	NM_001272003.2	c.30G>A	p.Pro10=	synonymous_variant	1/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNT1	ENST00000371757.7	c.30G>A	p.Pro10=	synonymous_variant	1/31	1	NM_020822.3	A2

Frequencies

GnomAD3 genomes AF: 0.00524 AC: 797 AN: 152038 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00989

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00406

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.00719

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00672 AC: 1581 AN: 235382 Hom.: 9 AF XY: 0.00764 AC XY: 992 AN XY: 129928

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.000925

Gnomad SAS exome AF: 0.0149

Gnomad FIN exome AF: 0.000424

Gnomad NFE exome AF: 0.00740

Gnomad OTH exome AF: 0.00749

GnomAD4 exome AF: 0.00813 AC: 11846 AN: 1456432 Hom.: 82 Cov.: 32 AF XY: 0.00842 AC XY: 6102 AN XY: 724562

Gnomad4 AFR exome AF: 0.00169

Gnomad4 AMR exome AF: 0.00357

Gnomad4 ASJ exome AF: 0.0155

Gnomad4 EAS exome AF: 0.0145

Gnomad4 SAS exome AF: 0.0146

Gnomad4 FIN exome AF: 0.000347

Gnomad4 NFE exome AF: 0.00788

Gnomad4 OTH exome AF: 0.00788

GnomAD4 genome AF: 0.00522 AC: 795 AN: 152156 Hom.: 5 Cov.: 33 AF XY: 0.00531 AC XY: 395 AN XY: 74406

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.00407

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00718

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00401 Hom.: 1

Bravo AF: 0.00519

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 30, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Developmental and epileptic encephalopathy, 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Autosomal dominant nocturnal frontal lobe epilepsy 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	2.3
Dann	Benign	0.80

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: rs139034501; hg19: chr9-138594134; COSMIC: COSV100039855; COSMIC: COSV100039855;