Genetic Variant ENST00000460750.5:n.-16C>A (chr9-135702197-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000460750.5(KCNT1):n.-62G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000368 in 1,085,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Consequence

KCNT1
ENST00000460750.5 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0730

Publications

0 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):

ovarian dysgenesis 5
Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
KCNT1	NM_020822.3 link	c.-62G>A	5_prime_UTR_variant	Exon 1 of 31	ENST00000371757.7	NP_065873.2	Q5JUK3-3
KCNT1	NM_001272003.2 link	c.-62G>A	5_prime_UTR_variant	Exon 1 of 31		NP_001258932.1	Q5JUK3-4
SOHLH1	XM_011518698.4 link	c.-2093C>T	upstream_gene_variant			XP_011517000.1
SOHLH1	XM_006717109.5 link	c.-2222C>T	upstream_gene_variant			XP_006717172.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7 link	c.-62G>A		5_prime_UTR_variant	Exon 1 of 31	1	NM_020822.3	ENSP00000360822.2		Q5JUK3-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000368

AC:

AN:

1085528

Hom.:

Cov.:

AF XY:

0.00000360

AC XY:

AN XY:

555606

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23960

American (AMR)

AF:

0.00

AC:

AN:

34824

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22456

East Asian (EAS)

AF:

0.00

AC:

AN:

35810

South Asian (SAS)

AF:

0.00

AC:

AN:

75604

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50484

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4902

European-Non Finnish (NFE)

AF:

0.00000506

AC:

AN:

790036

Other (OTH)

AF:

0.00

AC:

AN:

47452

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.637

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

6.1

(source)

DANN

Benign

0.83

PhyloP100

-0.073

PromoterAI

0.054

Neutral

(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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ENST00000460750.5:n.-16C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over