rs139034501

Variant names:

• chr9-135702288-G-A
• rs139034501
• NM_020822.3:c.30G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-135702288-G-A
• chr9-135702288-G-C
• chr9-135702288-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020822.3(KCNT1):​c.30G>A​(p.Pro10Pro) 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:12
• Conservation: PhyloP100: -1.43
• Publications: 4 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: Benign. The variant received -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 VariationId is 193440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 795 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.30G>A	p.Pro10Pro	synonymous	Exon 1 of 31	NP_065873.2
	KCNT1	NM_001272003.2		c.30G>A	p.Pro10Pro	synonymous	Exon 1 of 31	NP_001258932.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT1	ENST00000371757.7	TSL:1 MANE Select	c.30G>A	p.Pro10Pro	synonymous	Exon 1 of 31	ENSP00000360822.2
	KCNT1	ENST00000460750.5	TSL:1	n.30G>A		non_coding_transcript_exon	Exon 1 of 32	ENSP00000418777.1
	KCNT1	ENST00000487664.5	TSL:5	c.30G>A	p.Pro10Pro	synonymous	Exon 1 of 32	ENSP00000417851.2

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

GnomAD2 exomes AF: 0.00672 AC: 1581 AN: 235382 AF XY: 0.00764

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 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

African (AFR) AF: 0.00169 AC: 56 AN: 33108

American (AMR) AF: 0.00357 AC: 159 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.0155 AC: 402 AN: 25934

East Asian (EAS) AF: 0.0145 AC: 572 AN: 39370

South Asian (SAS) AF: 0.0146 AC: 1254 AN: 86074

European-Finnish (FIN) AF: 0.000347 AC: 18 AN: 51802

Middle Eastern (MID) AF: 0.0298 AC: 170 AN: 5714

European-Non Finnish (NFE) AF: 0.00788 AC: 8741 AN: 1109792

Other (OTH) AF: 0.00788 AC: 474 AN: 60140

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

African (AFR) AF: 0.00123 AC: 51 AN: 41530

American (AMR) AF: 0.00464 AC: 71 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3466

East Asian (EAS) AF: 0.00407 AC: 21 AN: 5156

South Asian (SAS) AF: 0.0162 AC: 78 AN: 4824

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10612

Middle Eastern (MID) AF: 0.0342 AC: 10 AN: 292

European-Non Finnish (NFE) AF: 0.00718 AC: 488 AN: 67958

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00401 Hom.: 1

Bravo AF: 0.00519

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)
-	-	1	Developmental and epileptic encephalopathy, 14 (1)
-	-	1	Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.3
DANN	Benign	0.80
PhyloP100		-1.4
PromoterAI		-0.0084	Neutral
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

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