rs759060806

Variant names:

• chr9-135784516-T-C
• rs759060806
• NM_020822.3:c.2944-19T>C

Your query was ambiguous. Multiple possible variants found:

• chr9-135784516-T-C
• chr9-135784516-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_020822.3(KCNT1):​c.2944-19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (0 hom., cov: 0)
  • Exomes 𝑓: 0.15 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNT1 NM_020822.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.369
• 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]

KCNT1 Gene-Disease associations (from GenCC):

• childhood-onset epilepsy syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 14

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• autosomal dominant nocturnal frontal lobe epilepsy 5

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 9-135784516-T-C is Benign according to our data. Variant chr9-135784516-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2944-19T>C		intron	N/A	NP_065873.2	Q5JUK3-3
	KCNT1	NM_001272003.2		c.2809-19T>C		intron	N/A	NP_001258932.1	Q5JUK3-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT1	ENST00000371757.7	TSL:1 MANE Select	c.2944-19T>C		intron	N/A	ENSP00000360822.2	Q5JUK3-3
	KCNT1	ENST00000460750.5	TSL:1	n.*2554-19T>C		intron	N/A	ENSP00000418777.1	F8WC49
	KCNT1	ENST00000487664.5	TSL:5	c.2944-19T>C		intron	N/A	ENSP00000417851.2	Q5JUK3-2

Frequencies

GnomAD3 genomes AF: 0.0516 AC: 1176 AN: 22810 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0421

Gnomad AMI AF: 0.0556

Gnomad AMR AF: 0.0404

Gnomad ASJ AF: 0.0500

Gnomad EAS AF: 0.0294

Gnomad SAS AF: 0.0348

Gnomad FIN AF: 0.0807

Gnomad MID AF: 0.0769

Gnomad NFE AF: 0.0586

Gnomad OTH AF: 0.0467

GnomAD2 exomes AF: 0.122 AC: 4388 AN: 35912 AF XY: 0.118

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.0520

Gnomad EAS exome AF: 0.272

Gnomad FIN exome AF: 0.0199

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.159

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.149 AC: 18140 AN: 121982 Hom.: 0 Cov.: 0 AF XY: 0.152 AC XY: 10010 AN XY: 65644

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0766 AC: 158 AN: 2064

American (AMR) AF: 0.174 AC: 890 AN: 5120

Ashkenazi Jewish (ASJ) AF: 0.0771 AC: 305 AN: 3954

East Asian (EAS) AF: 0.0563 AC: 321 AN: 5706

South Asian (SAS) AF: 0.247 AC: 4287 AN: 17350

European-Finnish (FIN) AF: 0.0563 AC: 1082 AN: 19224

Middle Eastern (MID) AF: 0.136 AC: 66 AN: 484

European-Non Finnish (NFE) AF: 0.163 AC: 10151 AN: 62214

Other (OTH) AF: 0.150 AC: 880 AN: 5866

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0514 AC: 1176 AN: 22860 Hom.: 0 Cov.: 0 AF XY: 0.0484 AC XY: 554 AN XY: 11440

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0418 AC: 268 AN: 6404

American (AMR) AF: 0.0403 AC: 121 AN: 3006

Ashkenazi Jewish (ASJ) AF: 0.0500 AC: 27 AN: 540

East Asian (EAS) AF: 0.0293 AC: 11 AN: 376

South Asian (SAS) AF: 0.0345 AC: 19 AN: 550

European-Finnish (FIN) AF: 0.0807 AC: 116 AN: 1438

Middle Eastern (MID) AF: 0.0769 AC: 2 AN: 26

European-Non Finnish (NFE) AF: 0.0586 AC: 590 AN: 10062

Other (OTH) AF: 0.0462 AC: 17 AN: 368

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)
-	-	1	Developmental and epileptic encephalopathy, 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.6
DANN	Benign	0.40
PhyloP100		-0.37
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs759060806;

hg19: chr9-138676362;