rs928573902

chr19-50328956-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004977.3(KCNC3):c.127C>T(p.Pro43Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000245 in 877,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: KCNC3 NM_004977.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0480

Genes affected

KCNC3 (HGNC:6235): (potassium voltage-gated channel subfamily C member 3) The Shaker gene family of Drosophila encodes components of voltage-gated potassium channels and is comprised of four subfamilies. Based on sequence similarity, this gene is similar to one of these subfamilies, namely the Shaw subfamily. The protein encoded by this gene belongs to the delayed rectifier class of channel proteins and is an integral membrane protein that mediates the voltage-dependent potassium ion permeability of excitable membranes. Alternate splicing results in several transcript variants. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031967282).
• BP6: Variant 19-50328956-G-A is Benign according to our data. Variant chr19-50328956-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 447619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000985 (144/146212) while in subpopulation AFR AF= 0.00333 (136/40790). AF 95% confidence interval is 0.00288. There are 0 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 140 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNC3	NM_004977.3	c.127C>T	p.Pro43Ser	missense_variant	1/5	ENST00000477616.2
KCNC3	NM_001372305.1	c.-102C>T		5_prime_UTR_variant	1/5
KCNC3	NR_110912.2	n.68+4513C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNC3	ENST00000477616.2	c.127C>T	p.Pro43Ser	missense_variant	1/5	1	NM_004977.3
KCNC3	ENST00000670667.1	c.127C>T	p.Pro43Ser	missense_variant	1/4			P3
KCNC3	ENST00000376959.6	c.127C>T	p.Pro43Ser	missense_variant	1/5	5		A2
KCNC3	ENST00000474951.1	c.-75+4513C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.000958 AC: 140 AN: 146122 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000339

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00150

GnomAD4 exome AF: 0.0000971 AC: 71 AN: 731360 Hom.: 0 Cov.: 10 AF XY: 0.0000992 AC XY: 35 AN XY: 352716

Gnomad4 AFR exome AF: 0.00385

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000109

Gnomad4 OTH exome AF: 0.000378

GnomAD4 genome AF: 0.000985 AC: 144 AN: 146212 Hom.: 0 Cov.: 24 AF XY: 0.000928 AC XY: 66 AN XY: 71140

Gnomad4 AFR AF: 0.00333

Gnomad4 AMR AF: 0.000339

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00149

Alfa AF: 0.00135 Hom.: 0

Bravo AF: 0.00122

ClinVar

Significance: Benign/Likely 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

Athena Diagnostics

Apr 13, 2017

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	17
Dann	Benign	0.97
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.42	T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.032	T;T
MetaSVM	Uncertain	-0.19	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.73	N;N
REVEL	Benign	0.27
Sift	Benign	0.039	D;D
Sift4G	Benign	0.60	T;T
Polyphen		0.0	.;B
Vest4		0.14
MutPred		0.21		Gain of phosphorylation at P43 (P = 0.011);Gain of phosphorylation at P43 (P = 0.011);
MVP		0.57
ClinPred		0.077	T
GERP RS		-1.1
Varity_R		0.047
gMVP		0.14

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: rs928573902; hg19: chr19-50832213;