9-135786407-G-A

Variant names:

• chr9-135786407-G-A
• rs138421850
• NM_020822.3:c.3388G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020822.3(KCNT1):​c.3388G>A​(p.Ala1130Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,576,966 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. A1130V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0098 (15 hom., cov: 33)
  • Exomes 𝑓: 0.013 (144 hom.)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.13
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004505396).
• BP6: Variant 9-135786407-G-A is Benign according to our data. Variant chr9-135786407-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00978 (1489/152318) while in subpopulation AMR AF = 0.0142 (217/15312). AF 95% confidence interval is 0.0126. There are 15 homozygotes in GnomAd4. There are 747 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1489 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.3388G>A	p.Ala1130Thr	missense	Exon 29 of 31	NP_065873.2	Q5JUK3-3
	KCNT1	NM_001272003.2		c.3253G>A	p.Ala1085Thr	missense	Exon 28 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.3388G>A	p.Ala1130Thr	missense	Exon 29 of 31	ENSP00000360822.2	Q5JUK3-3
	KCNT1	ENST00000460750.5	TSL:1	n.*2998G>A		non_coding_transcript_exon	Exon 29 of 32	ENSP00000418777.1	F8WC49
	KCNT1	ENST00000460750.5	TSL:1	n.*2998G>A		3_prime_UTR	Exon 29 of 32	ENSP00000418777.1	F8WC49

Frequencies

GnomAD3 genomes AF: 0.00980 AC: 1491 AN: 152202 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0104 AC: 1844 AN: 176890 AF XY: 0.0106

Gnomad AFR exome AF: 0.00315

Gnomad AMR exome AF: 0.00814

Gnomad ASJ exome AF: 0.00845

Gnomad EAS exome AF: 0.0000745

Gnomad FIN exome AF: 0.0148

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.0126 AC: 17924 AN: 1424648 Hom.: 144 Cov.: 36 AF XY: 0.0125 AC XY: 8818 AN XY: 705736

African (AFR) AF: 0.00199 AC: 65 AN: 32602

American (AMR) AF: 0.00988 AC: 393 AN: 39766

Ashkenazi Jewish (ASJ) AF: 0.00772 AC: 197 AN: 25512

East Asian (EAS) AF: 0.00 AC: 0 AN: 37690

South Asian (SAS) AF: 0.00887 AC: 732 AN: 82522

European-Finnish (FIN) AF: 0.0136 AC: 665 AN: 48808

Middle Eastern (MID) AF: 0.0163 AC: 78 AN: 4780

European-Non Finnish (NFE) AF: 0.0137 AC: 15023 AN: 1094112

Other (OTH) AF: 0.0131 AC: 771 AN: 58856

GnomAD4 genome AF: 0.00978 AC: 1489 AN: 152318 Hom.: 15 Cov.: 33 AF XY: 0.0100 AC XY: 747 AN XY: 74482

African (AFR) AF: 0.00284 AC: 118 AN: 41588

American (AMR) AF: 0.0142 AC: 217 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00911 AC: 44 AN: 4828

European-Finnish (FIN) AF: 0.0121 AC: 128 AN: 10622

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0133 AC: 902 AN: 68006

Other (OTH) AF: 0.0184 AC: 39 AN: 2116

Alfa AF: 0.00751 Hom.: 8

Bravo AF: 0.00951

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00246 AC: 10

ESP6500EA AF: 0.0106 AC: 85

ExAC AF: 0.00790 AC: 909

Asia WGS AF: 0.00491 AC: 17 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Autosomal dominant nocturnal frontal lobe epilepsy 5 (2)
-	-	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
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.0
DANN	Benign	0.90
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.028
Sift	Uncertain	0.012	D
Sift4G	Benign	0.45	T
Vest4		0.25
MPC		0.092
ClinPred		0.0033	T
GERP RS		-1.1
Varity_R		0.028
gMVP		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

Other links and lift over

dbSNP: rs138421850; hg19: chr9-138678253; COSMIC: COSV53712185; COSMIC: COSV53712185;