chr20-49373023-C-A

Variant names:

• chr20-49373023-C-A
• rs1386449842
• NM_004975.4:c.2537G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004975.4(KCNB1):​c.2537G>T​(p.Gly846Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,461,504 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G846R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: KCNB1 NM_004975.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.17
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000290421 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 22 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004975.4. 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
	KCNB1	NM_004975.4	MANE Select	c.2537G>T	p.Gly846Val	missense	Exon 2 of 2	NP_004966.1	Q14721

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNB1	ENST00000371741.6	TSL:1 MANE Select	c.2537G>T	p.Gly846Val	missense	Exon 2 of 2	ENSP00000360806.3	Q14721
	KCNB1	ENST00000635465.1	TSL:1	c.2537G>T	p.Gly846Val	missense	Exon 3 of 3	ENSP00000489193.1	Q14721
	KCNB1	ENST00000635878.1	TSL:5	c.97-73640G>T		intron	N/A	ENSP00000489908.1	A0A1B0GU02

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 250818 AF XY: 0.00

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: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461504 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727076

African (AFR) AF: 0.0000299 AC: 1 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5706

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111834

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy, 26 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.81	L
PhyloP100		5.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.47
MutPred		0.58		Loss of disorder (P = 0.0259)
MVP		0.58
MPC		0.78
ClinPred		0.81	D
GERP RS		5.0
Varity_R		0.37
gMVP		0.84
Mutation Taster		=73/27	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: rs1386449842; hg19: chr20-47989560;