NM_004975.4:c.568-38862T>C

Variant names:

• chr20-49413854-A-G
• rs237454
• NM_004975.4:c.568-38862T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004975.4(KCNB1):​c.568-38862T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 151,972 control chromosomes in the GnomAD database, including 6,867 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (6867 hom., cov: 32)
• Consequence: KCNB1 NM_004975.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNB1	NM_004975.4	c.568-38862T>C		intron_variant	Intron 1 of 1	ENST00000371741.6	NP_004966.1
KCNB1	XM_011528799.3	c.568-38862T>C		intron_variant	Intron 2 of 2		XP_011527101.1
LOC105372649	XR_001754659.2	n.1202-12798A>G		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNB1	ENST00000371741.6	c.568-38862T>C		intron_variant	Intron 1 of 1	1	NM_004975.4	ENSP00000360806.3
KCNB1	ENST00000635465.1	c.568-38862T>C		intron_variant	Intron 2 of 2	1		ENSP00000489193.1
KCNB1	ENST00000635878.1	c.96+68060T>C		intron_variant	Intron 1 of 2	5		ENSP00000489908.1
ENSG00000290421	ENST00000637341.1	n.207-9238A>G		intron_variant	Intron 2 of 7	5

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43205 AN: 151852 Hom.: 6868 Cov.: 32

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.434

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.341

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.284 AC: 43214 AN: 151972 Hom.: 6867 Cov.: 32 AF XY: 0.290 AC XY: 21506 AN XY: 74274

African (AFR) AF: 0.159 AC: 6574 AN: 41444

American (AMR) AF: 0.434 AC: 6627 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1329 AN: 3464

East Asian (EAS) AF: 0.482 AC: 2485 AN: 5154

South Asian (SAS) AF: 0.263 AC: 1264 AN: 4812

European-Finnish (FIN) AF: 0.360 AC: 3808 AN: 10566

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.296 AC: 20142 AN: 67946

Other (OTH) AF: 0.340 AC: 717 AN: 2106

Alfa AF: 0.297 Hom.: 18524

Bravo AF: 0.287

Asia WGS AF: 0.367 AC: 1274 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.087
DANN	Benign	0.60
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs237454; hg19: chr20-48030391;