chr20-49374378-C-T

Position:

• chr20-49374378-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004975.4(KCNB1):​c.1182G>A​(p.Gly394Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,612,992 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (13 hom.)
• Consequence: KCNB1 NM_004975.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.583

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]

ENSG00000290421 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 20-49374378-C-T is Benign according to our data. Variant chr20-49374378-C-T is described in ClinVar as [Benign]. Clinvar id is 383248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.583 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00441 (671/152316) while in subpopulation AFR AF= 0.0129 (537/41562). AF 95% confidence interval is 0.012. There are 2 homozygotes in gnomad4. There are 322 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 671 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNB1	NM_004975.4	c.1182G>A	p.Gly394Gly	synonymous_variant	2/2	ENST00000371741.6	NP_004966.1
KCNB1	XM_011528799.3	c.1182G>A	p.Gly394Gly	synonymous_variant	3/3		XP_011527101.1
LOC105372649	XR_001754659.2	n.1201+42354C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNB1	ENST00000371741.6	c.1182G>A	p.Gly394Gly	synonymous_variant	2/2	1	NM_004975.4	ENSP00000360806.3
KCNB1	ENST00000635465.1	c.1182G>A	p.Gly394Gly	synonymous_variant	3/3	1		ENSP00000489193.1
KCNB1	ENST00000635878.1	c.97-74995G>A		intron_variant		5		ENSP00000489908.1
ENSG00000290421	ENST00000637341.1	n.206+42354C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00440 AC: 670 AN: 152198 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000411

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00213 AC: 533 AN: 250070 Hom.: 7 AF XY: 0.00185 AC XY: 250 AN XY: 135314

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.0159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000520

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00111 AC: 1625 AN: 1460676 Hom.: 13 Cov.: 33 AF XY: 0.00105 AC XY: 762 AN XY: 726720

Gnomad4 AFR exome AF: 0.0163

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.0151

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000376

Gnomad4 OTH exome AF: 0.00258

GnomAD4 genome AF: 0.00441 AC: 671 AN: 152316 Hom.: 2 Cov.: 32 AF XY: 0.00432 AC XY: 322 AN XY: 74478

Gnomad4 AFR AF: 0.0129

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00365 Hom.: 0

Bravo AF: 0.00568

EpiCase AF: 0.00125

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 25, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	KCNB1: BP4, BP7, BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 21, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Developmental and epileptic encephalopathy, 26 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	3.3
DANN	Benign	0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs77238446; hg19: chr20-47990915;