NM_004975.4:c.567+887T>C

Variant names:

• chr20-49481027-A-G
• rs553213
• NM_004975.4:c.567+887T>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+887T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.62 in 151,824 control chromosomes in the GnomAD database, including 29,738 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 0.62 (29738 hom., cov: 30)
• Consequence: KCNB1 NM_004975.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.33
• 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.686 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNB1	NM_004975.4	MANE Select	c.567+887T>C		intron	N/A	NP_004966.1	Q14721

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNB1	ENST00000371741.6	TSL:1 MANE Select	c.567+887T>C		intron	N/A	ENSP00000360806.3	Q14721
	KCNB1	ENST00000635465.1	TSL:1	c.567+887T>C		intron	N/A	ENSP00000489193.1	Q14721
	KCNB1	ENST00000635878.1	TSL:5	c.96+887T>C		intron	N/A	ENSP00000489908.1	A0A1B0GU02

Frequencies

GnomAD3 genomes AF: 0.620 AC: 94085 AN: 151706 Hom.: 29695 Cov.: 30

Gnomad AFR AF: 0.692

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.666

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.654

Gnomad FIN AF: 0.561

Gnomad MID AF: 0.653

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.650

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

GnomAD4 genome AF: 0.620 AC: 94169 AN: 151824 Hom.: 29738 Cov.: 30 AF XY: 0.617 AC XY: 45778 AN XY: 74186

African (AFR) AF: 0.693 AC: 28673 AN: 41388

American (AMR) AF: 0.517 AC: 7887 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.666 AC: 2311 AN: 3470

East Asian (EAS) AF: 0.365 AC: 1879 AN: 5154

South Asian (SAS) AF: 0.656 AC: 3143 AN: 4792

European-Finnish (FIN) AF: 0.561 AC: 5909 AN: 10528

Middle Eastern (MID) AF: 0.661 AC: 193 AN: 292

European-Non Finnish (NFE) AF: 0.625 AC: 42437 AN: 67936

Other (OTH) AF: 0.645 AC: 1357 AN: 2104

Alfa AF: 0.619 Hom.: 10056

Bravo AF: 0.616

Asia WGS AF: 0.511 AC: 1772 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.22
DANN	Benign	0.43
PhyloP100		-2.3
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: rs553213; hg19: chr20-48097564;