rs766596568

Variant names:

• chr20-49373209-G-A
• rs766596568
• NM_004975.4:c.2351C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4 BP6_Moderate BS2

The NM_004975.4(KCNB1):​c.2351C>T​(p.Pro784Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,892 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 (★). Synonymous variant affecting the same amino acid position (i.e. P784P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: KCNB1 NM_004975.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.75
• Publications: 3 publications found

Genes affected

KCNB1 (HGNC:6231): (potassium voltage-gated channel subfamily B member 1) Voltage-gated potassium (Kv) 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. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shab-related subfamily. This member is a delayed rectifier potassium channel and its activity is modulated by some other family members. [provided by RefSeq, Jul 2008]

KCNB1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 26

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000290421 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29145536).
• BP6: Variant 20-49373209-G-A is Benign according to our data. Variant chr20-49373209-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 576386.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNB1	NM_004975.4	c.2351C>T	p.Pro784Leu	missense_variant	Exon 2 of 2	ENST00000371741.6	NP_004966.1
KCNB1	XM_011528799.3	c.2351C>T	p.Pro784Leu	missense_variant	Exon 3 of 3		XP_011527101.1
LOC105372649	XR_001754659.2	n.1201+41185G>A		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNB1	ENST00000371741.6	c.2351C>T	p.Pro784Leu	missense_variant	Exon 2 of 2	1	NM_004975.4	ENSP00000360806.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251370 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 26 Benign:1

Sep 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	.;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	0.81	L;L
PhyloP100		7.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.6	N;.
REVEL	Uncertain	0.43
Sift	Benign	0.097	T;.
Sift4G	Benign	0.098	T;T
Polyphen		0.99	D;D
Vest4		0.27
MutPred		0.11		Loss of glycosylation at P784 (P = 0.0331);Loss of glycosylation at P784 (P = 0.0331);
MVP		0.56
MPC		0.55
ClinPred		0.47	T
GERP RS		5.6
Varity_R		0.11
gMVP		0.57
Mutation Taster		=47/53	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: rs766596568; hg19: chr20-47989746; COSMIC: COSV65567723; COSMIC: COSV65567723;