rs562954

Variant names:

• chr20-49475539-A-G
• rs562954
• NM_004975.4:c.567+6375T>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.567+6375T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 152,140 control chromosomes in the GnomAD database, including 12,010 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 0.40 (12010 hom., cov: 33)
• Consequence: KCNB1 NM_004975.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0900
• Publications: 17 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNB1	NM_004975.4	c.567+6375T>C		intron_variant	Intron 1 of 1	ENST00000371741.6	NP_004966.1
KCNB1	XM_011528799.3	c.567+6375T>C		intron_variant	Intron 2 of 2		XP_011527101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNB1	ENST00000371741.6	c.567+6375T>C		intron_variant	Intron 1 of 1	1	NM_004975.4	ENSP00000360806.3
KCNB1	ENST00000635465.1	c.567+6375T>C		intron_variant	Intron 2 of 2	1		ENSP00000489193.1
KCNB1	ENST00000635878.1	c.96+6375T>C		intron_variant	Intron 1 of 2	5		ENSP00000489908.1
KCNB1	ENST00000636950.1	n.87+6375T>C		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60114 AN: 152024 Hom.: 11978 Cov.: 33

Gnomad AFR AF: 0.444

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.413

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

GnomAD4 genome AF: 0.396 AC: 60191 AN: 152140 Hom.: 12010 Cov.: 33 AF XY: 0.397 AC XY: 29501 AN XY: 74352

African (AFR) AF: 0.445 AC: 18454 AN: 41484

American (AMR) AF: 0.356 AC: 5450 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 1513 AN: 3466

East Asian (EAS) AF: 0.220 AC: 1140 AN: 5178

South Asian (SAS) AF: 0.418 AC: 2015 AN: 4820

European-Finnish (FIN) AF: 0.359 AC: 3802 AN: 10588

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.391 AC: 26593 AN: 67990

Other (OTH) AF: 0.410 AC: 866 AN: 2114

Alfa AF: 0.393 Hom.: 39041

Bravo AF: 0.393

Asia WGS AF: 0.327 AC: 1134 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.45
DANN	Benign	0.45
PhyloP100		-0.090
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: rs562954; hg19: chr20-48092076;