chr9-135702317-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020822.3(KCNT1):c.59G>C(p.Gly20Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00787 in 1,610,946 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G20R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0052 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0081 ( 84 hom. )

Consequence

KCNT1
NM_020822.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.571

Publications

6 publications found

Variant links:

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]

KCNT1 links:

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]

SOHLH1 Gene-Disease associations (from GenCC):

spermatogenic failure 32
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
ovarian dysgenesis 5
Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hypogonadism
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

SOHLH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032934844).

BP6

Variant 9-135702317-G-C is Benign according to our data. Variant chr9-135702317-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0052 (792/152174) while in subpopulation SAS AF = 0.0162 (78/4826). AF 95% confidence interval is 0.0133. There are 5 homozygotes in GnomAd4. There are 392 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 792 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020822.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT1	NM_020822.3	MANE Select	c.59G>C	p.Gly20Ala	missense	Exon 1 of 31	NP_065873.2	Q5JUK3-3
	KCNT1	NM_001272003.2		c.59G>C	p.Gly20Ala	missense	Exon 1 of 31	NP_001258932.1	Q5JUK3-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNT1	ENST00000371757.7	TSL:1 MANE Select	c.59G>C	p.Gly20Ala	missense	Exon 1 of 31	ENSP00000360822.2	Q5JUK3-3
KCNT1	ENST00000460750.5	TSL:1	n.59G>C		non_coding_transcript_exon	Exon 1 of 32	ENSP00000418777.1	F8WC49
KCNT1	ENST00000487664.5	TSL:5	c.59G>C	p.Gly20Ala	missense	Exon 1 of 32	ENSP00000417851.2	Q5JUK3-2

Frequencies

GnomAD3 genomes

AF:

0.00522

AC:

794

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00464

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.00369

Gnomad SAS

AF:

0.0161

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00718

Gnomad OTH

AF:

0.00527

GnomAD2 exomes

AF:

0.00663

AC:

1603

AN:

241640

AF XY:

0.00758

show subpopulations

Gnomad AFR exome

AF:

0.00120

Gnomad AMR exome

AF:

0.00367

Gnomad ASJ exome

AF:

0.0153

Gnomad EAS exome

AF:

0.000952

Gnomad FIN exome

AF:

0.000420

Gnomad NFE exome

AF:

0.00731

Gnomad OTH exome

AF:

0.00761

GnomAD4 exome

AF:

0.00815

AC:

11886

AN:

1458772

Hom.:

Cov.:

AF XY:

0.00844

AC XY:

6124

AN XY:

725746

show subpopulations

African (AFR)

AF:

0.00168

AC:

AN:

33338

American (AMR)

AF:

0.00358

AC:

160

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.0155

AC:

403

AN:

26042

East Asian (EAS)

AF:

0.0145

AC:

576

AN:

39592

South Asian (SAS)

AF:

0.0147

AC:

1267

AN:

86190

European-Finnish (FIN)

AF:

0.000346

AC:

AN:

51980

Middle Eastern (MID)

AF:

0.0298

AC:

171

AN:

5740

European-Non Finnish (NFE)

AF:

0.00788

AC:

8759

AN:

1111006

Other (OTH)

AF:

0.00790

AC:

476

AN:

60252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

612

1224

1836

2448

3060

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

354

708

1062

1416

1770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00520

AC:

792

AN:

152174

Hom.:

Cov.:

AF XY:

0.00527

AC XY:

392

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

41538

American (AMR)

AF:

0.00464

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

AN:

3470

East Asian (EAS)

AF:

0.00370

AC:

AN:

5138

South Asian (SAS)

AF:

0.0162

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00717

AC:

487

AN:

67964

Other (OTH)

AF:

0.00522

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

126

168

210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00599

Hom.:

Bravo

AF:

0.00520

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00688

AC:

ExAC

AF:

0.00630

AC:

759

EpiCase

AF:

0.00763

EpiControl

AF:

0.00982

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (3)

Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)

Developmental and epileptic encephalopathy, 14 (1)

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

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.77

CADD

Benign

5.1

(source)

DANN

Benign

0.72

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0033

MetaSVM

Benign

-0.97

PhyloP100

-0.57

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.95

REVEL

Benign

0.048

Sift

Benign

0.33

Sift4G

Pathogenic

0.0

Vest4

0.15

MVP

0.030

MPC

0.68

ClinPred

0.0026

GERP RS

0.96

PromoterAI

0.0052

Neutral

(source)

gMVP

0.088

Mutation Taster

=97/3

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over