Genetic Variant NM_020822.3:c.99A>G (chr9-135702357-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_020822.3(KCNT1):c.99A>G(p.Gln33Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00263 in 1,610,794 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 7 hom. )

Consequence

KCNT1
NM_020822.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -0.149

Publications

2 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 9-135702357-A-G is Benign according to our data. Variant chr9-135702357-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193439.

BP7

Synonymous conserved (PhyloP=-0.149 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00314 (477/151724) while in subpopulation AFR AF = 0.00454 (188/41368). AF 95% confidence interval is 0.00401. There are 3 homozygotes in GnomAd4. There are 226 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 477 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.99A>G	p.Gln33Gln	synonymous	Exon 1 of 31	NP_065873.2	Q5JUK3-3
	KCNT1	NM_001272003.2		c.99A>G	p.Gln33Gln	synonymous	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.99A>G	p.Gln33Gln	synonymous	Exon 1 of 31	ENSP00000360822.2	Q5JUK3-3
KCNT1	ENST00000460750.5	TSL:1	n.99A>G		non_coding_transcript_exon	Exon 1 of 32	ENSP00000418777.1	F8WC49
KCNT1	ENST00000487664.5	TSL:5	c.99A>G	p.Gln33Gln	synonymous	Exon 1 of 32	ENSP00000417851.2	Q5JUK3-2

Frequencies

GnomAD3 genomes

AF:

0.00313

AC:

475

AN:

151608

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00451

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00269

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00157

Gnomad SAS

AF:

0.000624

Gnomad FIN

AF:

0.000379

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00312

Gnomad OTH

AF:

0.00385

GnomAD2 exomes

AF:

0.00209

AC:

513

AN:

244966

AF XY:

0.00208

show subpopulations

Gnomad AFR exome

AF:

0.00407

Gnomad AMR exome

AF:

0.00160

Gnomad ASJ exome

AF:

0.00252

Gnomad EAS exome

AF:

0.000717

Gnomad FIN exome

AF:

0.000418

Gnomad NFE exome

AF:

0.00284

Gnomad OTH exome

AF:

0.00315

GnomAD4 exome

AF:

0.00257

AC:

3753

AN:

1459070

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

1853

AN XY:

725912

show subpopulations

African (AFR)

AF:

0.00559

AC:

187

AN:

33424

American (AMR)

AF:

0.00175

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00334

AC:

AN:

26082

East Asian (EAS)

AF:

0.00391

AC:

155

AN:

39658

South Asian (SAS)

AF:

0.000615

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.000346

AC:

AN:

52062

Middle Eastern (MID)

AF:

0.00262

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00272

AC:

3022

AN:

1110942

Other (OTH)

AF:

0.00229

AC:

138

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

183

367

550

734

917

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

224

336

448

560

<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:

0.00314

AC:

477

AN:

151724

Hom.:

Cov.:

AF XY:

0.00305

AC XY:

226

AN XY:

74184

show subpopulations

African (AFR)

AF:

0.00454

AC:

188

AN:

41368

American (AMR)

AF:

0.00268

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.00157

AC:

AN:

5080

South Asian (SAS)

AF:

0.000625

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.000379

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00312

AC:

212

AN:

67846

Other (OTH)

AF:

0.00381

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00305

Hom.:

Bravo

AF:

0.00344

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00382

EpiControl

AF:

0.00410

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

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

BayesDel_noAF

Benign

-0.87

CADD

Benign

2.9

(source)

DANN

Benign

0.29

PhyloP100

-0.15

PromoterAI

0.0087

Neutral

(source)

Mutation Taster

=100/0

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

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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