20-49373029-A-G

Variant names:

• chr20-49373029-A-G
• rs1314041160
• NM_004975.4:c.2531T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_004975.4(KCNB1):​c.2531T>C​(p.Leu844Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,742 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 Benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: KCNB1 NM_004975.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.33
• 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: 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21908373).
• BP6: Variant 20-49373029-A-G is Benign according to our data. Variant chr20-49373029-A-G is described in ClinVar as [Benign]. Clinvar id is 1502238.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNB1	NM_004975.4	c.2531T>C	p.Leu844Ser	missense_variant	Exon 2 of 2	ENST00000371741.6	NP_004966.1
KCNB1	XM_011528799.3	c.2531T>C	p.Leu844Ser	missense_variant	Exon 3 of 3		XP_011527101.1
LOC105372649	XR_001754659.2	n.1201+41005A>G		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNB1	ENST00000371741.6	c.2531T>C	p.Leu844Ser	missense_variant	Exon 2 of 2	1	NM_004975.4	ENSP00000360806.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251088 AF XY: 0.00000737

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461742 Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 727168

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 26 Benign:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.25	T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.042
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.55	.;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.46	N;N
PhyloP100		3.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.59	N;.
REVEL	Uncertain	0.57
Sift	Benign	0.30	T;.
Sift4G	Benign	0.25	T;T
Polyphen		0.020	B;B
Vest4		0.47
MutPred		0.37		Gain of glycosylation at L844 (P = 0.0054);Gain of glycosylation at L844 (P = 0.0054);
MVP		0.82
MPC		0.26
ClinPred		0.15	T
GERP RS		5.6
Varity_R		0.11
gMVP		0.62
Mutation Taster		=84/16	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: rs1314041160; hg19: chr20-47989566;