chr9-135784592-A-G

Variant names:

• chr9-135784592-A-G
• rs143780942
• NM_020822.3:c.3001A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 2P and 14B. PM5 BP4_Moderate BP6_Very_Strong BS2

The NM_020822.3(KCNT1):​c.3001A>G​(p.Thr1001Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,573,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1001M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 8.65
• Publications: 1 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: Orphanet, G2P
• 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.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-135784592-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1328519.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.111849576).
• BP6: Variant 9-135784592-A-G is Benign according to our data. Variant chr9-135784592-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 417214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 24 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.3001A>G	p.Thr1001Ala	missense	Exon 26 of 31	NP_065873.2	Q5JUK3-3
	KCNT1	NM_001272003.2		c.2866A>G	p.Thr956Ala	missense	Exon 25 of 31	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.3001A>G	p.Thr1001Ala	missense	Exon 26 of 31	ENSP00000360822.2	Q5JUK3-3
	KCNT1	ENST00000460750.5	TSL:1	n.*2611A>G		non_coding_transcript_exon	Exon 26 of 32	ENSP00000418777.1	F8WC49
	KCNT1	ENST00000460750.5	TSL:1	n.*2611A>G		3_prime_UTR	Exon 26 of 32	ENSP00000418777.1	F8WC49

Frequencies

GnomAD3 genomes AF: 0.000165 AC: 24 AN: 145640 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00117

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000195

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000323 AC: 79 AN: 244396 AF XY: 0.000315

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00122

Gnomad NFE exome AF: 0.000474

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.000214 AC: 306 AN: 1428126 Hom.: 0 Cov.: 34 AF XY: 0.000217 AC XY: 154 AN XY: 710104

African (AFR) AF: 0.00 AC: 0 AN: 32572

American (AMR) AF: 0.00 AC: 0 AN: 43514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24962

East Asian (EAS) AF: 0.00 AC: 0 AN: 36904

South Asian (SAS) AF: 0.00 AC: 0 AN: 85724

European-Finnish (FIN) AF: 0.00125 AC: 62 AN: 49602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4608

European-Non Finnish (NFE) AF: 0.000193 AC: 211 AN: 1092058

Other (OTH) AF: 0.000567 AC: 33 AN: 58182

GnomAD4 genome AF: 0.000165 AC: 24 AN: 145640 Hom.: 0 Cov.: 31 AF XY: 0.000227 AC XY: 16 AN XY: 70558

African (AFR) AF: 0.00 AC: 0 AN: 39488

American (AMR) AF: 0.00 AC: 0 AN: 14256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3406

East Asian (EAS) AF: 0.00 AC: 0 AN: 4718

South Asian (SAS) AF: 0.00 AC: 0 AN: 4400

European-Finnish (FIN) AF: 0.00117 AC: 11 AN: 9404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 298

European-Non Finnish (NFE) AF: 0.000195 AC: 13 AN: 66760

Other (OTH) AF: 0.00 AC: 0 AN: 2024

Alfa AF: 0.000315 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000496 AC: 60

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.0075	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.040
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.1	L
PhyloP100		8.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.78	N
REVEL	Uncertain	0.37
Sift	Benign	0.47	T
Sift4G	Benign	0.50	T
Polyphen		0.38	B
Vest4		0.96
MVP		0.70
MPC		0.67
ClinPred		0.079	T
GERP RS		4.6
Varity_R		0.14
gMVP		0.93
Mutation Taster		=32/68	disease causing

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: rs143780942; hg19: chr9-138676438;