ENST00000460750.5:n.-27C>A

Variant names:

• chr9-135702186-G-A
• NM_020822.3:c.-73G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000460750.5(KCNT1):​n.-73G>A variant causes a upstream gene 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNT1 ENST00000460750.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.656
• Publications: 0 publications found

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]

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

ACMG classification

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=-0.81).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNT1	NM_020822.3	c.-73G>A		5_prime_UTR_variant	Exon 1 of 31	ENST00000371757.7	NP_065873.2
KCNT1	NM_001272003.2	c.-73G>A		5_prime_UTR_variant	Exon 1 of 31		NP_001258932.1
SOHLH1	XM_011518698.4	c.-2082C>T		upstream_gene_variant			XP_011517000.1
SOHLH1	XM_006717109.5	c.-2211C>T		upstream_gene_variant			XP_006717172.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7	c.-73G>A		5_prime_UTR_variant	Exon 1 of 31	1	NM_020822.3	ENSP00000360822.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1000638 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 516212

African (AFR) AF: 0.00 AC: 0 AN: 22128

American (AMR) AF: 0.00 AC: 0 AN: 34166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21876

East Asian (EAS) AF: 0.00 AC: 0 AN: 35328

South Asian (SAS) AF: 0.00 AC: 0 AN: 73926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4662

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 715094

Other (OTH) AF: 0.00 AC: 0 AN: 44606

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.0
DANN	Benign	0.77
PhyloP100		0.66
PromoterAI		0.021	Neutral
Mutation Taster		=299/1	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr9-138594032;