20-49422880-A-G

Variant names:

• chr20-49422880-A-G
• rs6019825
• NM_004975.4:c.568-47888T>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.568-47888T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 151,912 control chromosomes in the GnomAD database, including 25,985 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 0.57 (25985 hom., cov: 31)
• Consequence: KCNB1 NM_004975.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.208
• Publications: 4 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.764 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNB1	NM_004975.4	MANE Select	c.568-47888T>C		intron	N/A	NP_004966.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNB1	ENST00000371741.6	TSL:1 MANE Select	c.568-47888T>C		intron	N/A	ENSP00000360806.3
	KCNB1	ENST00000635465.1	TSL:1	c.568-47888T>C		intron	N/A	ENSP00000489193.1
	KCNB1	ENST00000635878.1	TSL:5	c.96+59034T>C		intron	N/A	ENSP00000489908.1

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86524 AN: 151794 Hom.: 25947 Cov.: 31

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.609

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.543

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.582

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

GnomAD4 genome AF: 0.570 AC: 86614 AN: 151912 Hom.: 25985 Cov.: 31 AF XY: 0.566 AC XY: 42013 AN XY: 74218

African (AFR) AF: 0.771 AC: 31956 AN: 41460

American (AMR) AF: 0.609 AC: 9285 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1958 AN: 3464

East Asian (EAS) AF: 0.543 AC: 2791 AN: 5142

South Asian (SAS) AF: 0.506 AC: 2433 AN: 4806

European-Finnish (FIN) AF: 0.406 AC: 4277 AN: 10524

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.473 AC: 32148 AN: 67946

Other (OTH) AF: 0.578 AC: 1221 AN: 2112

Alfa AF: 0.522 Hom.: 5329

Bravo AF: 0.592

Asia WGS AF: 0.564 AC: 1957 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	4.5
DANN	Benign	0.53
PhyloP100		0.21
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: rs6019825; hg19: chr20-48039417;