rs16994565

Variant names:

• chr20-49404537-T-C
• rs16994565
• NM_004975.4:c.568-29545A>G

Variant summary

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

The NM_004975.4(KCNB1):​c.568-29545A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 152,058 control chromosomes in the GnomAD database, including 1,443 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 0.11 (1443 hom., cov: 32)
• Consequence: KCNB1 NM_004975.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.302
• Publications: 2 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=-0.68).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNB1	NM_004975.4	c.568-29545A>G		intron_variant	Intron 1 of 1	ENST00000371741.6	NP_004966.1
KCNB1	XM_011528799.3	c.568-29545A>G		intron_variant	Intron 2 of 2		XP_011527101.1
LOC105372649	XR_001754659.2	n.1202-22115T>C		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNB1	ENST00000371741.6	c.568-29545A>G		intron_variant	Intron 1 of 1	1	NM_004975.4	ENSP00000360806.3
KCNB1	ENST00000635465.1	c.568-29545A>G		intron_variant	Intron 2 of 2	1		ENSP00000489193.1
KCNB1	ENST00000635878.1	c.96+77377A>G		intron_variant	Intron 1 of 2	5		ENSP00000489908.1
ENSG00000290421	ENST00000637341.1	n.207-18555T>C		intron_variant	Intron 2 of 7	5

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17229 AN: 151940 Hom.: 1431 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.0967

Gnomad AMR AF: 0.0856

Gnomad ASJ AF: 0.0536

Gnomad EAS AF: 0.0899

Gnomad SAS AF: 0.0835

Gnomad FIN AF: 0.0426

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0621

Gnomad OTH AF: 0.104

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

GnomAD4 genome AF: 0.114 AC: 17282 AN: 152058 Hom.: 1443 Cov.: 32 AF XY: 0.111 AC XY: 8263 AN XY: 74322

African (AFR) AF: 0.239 AC: 9913 AN: 41420

American (AMR) AF: 0.0854 AC: 1304 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0536 AC: 186 AN: 3472

East Asian (EAS) AF: 0.0900 AC: 466 AN: 5180

South Asian (SAS) AF: 0.0833 AC: 402 AN: 4824

European-Finnish (FIN) AF: 0.0426 AC: 451 AN: 10588

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0622 AC: 4228 AN: 67998

Other (OTH) AF: 0.103 AC: 218 AN: 2110

Alfa AF: 0.0836 Hom.: 172

Bravo AF: 0.121

Asia WGS AF: 0.105 AC: 368 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	13
DANN	Benign	0.74
PhyloP100		-0.30
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: rs16994565; hg19: chr20-48021074;