chr20-49444608-G-A

Variant names:

• chr20-49444608-G-A
• rs742759
• NM_004975.4:c.567+37306C>T

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+37306C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 151,998 control chromosomes in the GnomAD database, including 7,785 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 0.29 (7785 hom., cov: 32)
• Consequence: KCNB1 NM_004975.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.257
• Publications: 8 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.51 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.567+37306C>T		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.567+37306C>T		intron	N/A	ENSP00000360806.3
	KCNB1	ENST00000635465.1	TSL:1	c.567+37306C>T		intron	N/A	ENSP00000489193.1
	KCNB1	ENST00000635878.1	TSL:5	c.96+37306C>T		intron	N/A	ENSP00000489908.1

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43300 AN: 151880 Hom.: 7750 Cov.: 32

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.253

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

GnomAD4 genome AF: 0.285 AC: 43382 AN: 151998 Hom.: 7785 Cov.: 32 AF XY: 0.281 AC XY: 20865 AN XY: 74292

African (AFR) AF: 0.516 AC: 21360 AN: 41412

American (AMR) AF: 0.181 AC: 2763 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 616 AN: 3468

East Asian (EAS) AF: 0.144 AC: 745 AN: 5174

South Asian (SAS) AF: 0.255 AC: 1227 AN: 4816

European-Finnish (FIN) AF: 0.163 AC: 1723 AN: 10568

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.208 AC: 14122 AN: 67970

Other (OTH) AF: 0.250 AC: 528 AN: 2112

Alfa AF: 0.229 Hom.: 6316

Bravo AF: 0.295

Asia WGS AF: 0.223 AC: 774 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.31
PhyloP100		0.26
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: rs742759; hg19: chr20-48061145;