20-49373713-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004975.4(KCNB1):c.1847C>G(p.Thr616Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0183 in 1,614,164 control chromosomes in the GnomAD database, including 328 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T616I) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.015 (19 hom., cov: 32)
  • Exomes 𝑓: 0.019 (309 hom.)
• Consequence: KCNB1 NM_004975.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.96

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KCNB1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0023046434).
• BP6: Variant 20-49373713-G-C is Benign according to our data. Variant chr20-49373713-G-C is described in ClinVar as [Benign]. Clinvar id is 380823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-49373713-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0155 (2359/152282) while in subpopulation NFE AF= 0.0211 (1438/68014). AF 95% confidence interval is 0.0202. There are 19 homozygotes in gnomad4. There are 1215 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2361 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNB1	NM_004975.4	c.1847C>G	p.Thr616Ser	missense_variant	2/2	ENST00000371741.6
LOC105372649	XR_001754659.2	n.1201+41689G>C		intron_variant, non_coding_transcript_variant
KCNB1	XM_011528799.3	c.1847C>G	p.Thr616Ser	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNB1	ENST00000371741.6	c.1847C>G	p.Thr616Ser	missense_variant	2/2	1	NM_004975.4	P1
KCNB1	ENST00000635465.1	c.1847C>G	p.Thr616Ser	missense_variant	3/3	1		P1
	ENST00000637341.1	n.206+41689G>C		intron_variant, non_coding_transcript_variant		5
KCNB1	ENST00000635878.1	c.97-74330C>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2361 AN: 152164 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00357

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.0329

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.0154

GnomAD3 exomes AF: 0.0173 AC: 4347 AN: 250860 Hom.: 69 AF XY: 0.0183 AC XY: 2482 AN XY: 135732

Gnomad AFR exome AF: 0.00266

Gnomad AMR exome AF: 0.00841

Gnomad ASJ exome AF: 0.0290

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0195

Gnomad FIN exome AF: 0.0365

Gnomad NFE exome AF: 0.0197

Gnomad OTH exome AF: 0.0162

GnomAD4 exome AF: 0.0186 AC: 27151 AN: 1461882 Hom.: 309 Cov.: 33 AF XY: 0.0190 AC XY: 13810 AN XY: 727244

Gnomad4 AFR exome AF: 0.00236

Gnomad4 AMR exome AF: 0.00888

Gnomad4 ASJ exome AF: 0.0275

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0206

Gnomad4 FIN exome AF: 0.0315

Gnomad4 NFE exome AF: 0.0191

Gnomad4 OTH exome AF: 0.0186

GnomAD4 genome AF: 0.0155 AC: 2359 AN: 152282 Hom.: 19 Cov.: 32 AF XY: 0.0163 AC XY: 1215 AN XY: 74462

Gnomad4 AFR AF: 0.00356

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.0280

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0189

Gnomad4 FIN AF: 0.0329

Gnomad4 NFE AF: 0.0211

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0188 Hom.: 26

Bravo AF: 0.0125

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0189 AC: 73

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0197 AC: 169

ExAC AF: 0.0162 AC: 1969

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0208

EpiControl AF: 0.0211

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 29, 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

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 15, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	16
Dann	Benign	0.28
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.29	N
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.44	N;.
REVEL	Benign	0.11
Sift	Benign	0.71	T;.
Sift4G	Benign	0.81	T;T
Polyphen		0.0	B;B
Vest4		0.047
MutPred		0.090		Gain of glycosylation at T616 (P = 0.0255);Gain of glycosylation at T616 (P = 0.0255);
MPC		0.17
ClinPred		0.0064	T
GERP RS		5.0
Varity_R		0.057
gMVP		0.18

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: rs2229006; hg19: chr20-47990250;