4-20850543-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_025221.6(KCNIP4):c.288T>C(p.Asn96=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,610,388 control chromosomes in the GnomAD database, including 135,184 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (10443 hom., cov: 33)
  • Exomes 𝑓: 0.41 (124741 hom.)
• Consequence: KCNIP4 NM_025221.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.0002750
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.618

Genes affected

KCNIP4 (HGNC:30083): (potassium voltage-gated channel interacting protein 4) This gene encodes a member of the family of voltage-gated potassium (Kv) channel-interacting proteins (KCNIPs), which belong to the recoverin branch of the EF-hand superfamily. Members of the KCNIP family are small calcium binding proteins. They all have EF-hand-like domains, and differ from each other in the N-terminus. They are integral subunit components of native Kv4 channel complexes. They may regulate A-type currents, and hence neuronal excitability, in response to changes in intracellular calcium. This protein member also interacts with presenilin. Multiple alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 4-20850543-A-G is Benign according to our data. Variant chr4-20850543-A-G is described in ClinVar as [Benign]. Clinvar id is 3060067.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.618 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNIP4	NM_025221.6	c.288T>C	p.Asn96=	splice_region_variant, synonymous_variant	3/9	ENST00000382152.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNIP4	ENST00000382152.7	c.288T>C	p.Asn96=	splice_region_variant, synonymous_variant	3/9	5	NM_025221.6

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53548 AN: 151988 Hom.: 10433 Cov.: 33

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.412

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.420

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.410

Gnomad OTH AF: 0.374

GnomAD3 exomes AF: 0.415 AC: 103943 AN: 250332 Hom.: 22516 AF XY: 0.416 AC XY: 56287 AN XY: 135300

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.527

Gnomad ASJ exome AF: 0.425

Gnomad EAS exome AF: 0.417

Gnomad SAS exome AF: 0.406

Gnomad FIN exome AF: 0.439

Gnomad NFE exome AF: 0.413

Gnomad OTH exome AF: 0.421

GnomAD4 exome AF: 0.410 AC: 597867 AN: 1458282 Hom.: 124741 Cov.: 34 AF XY: 0.411 AC XY: 297810 AN XY: 725440

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.518

Gnomad4 ASJ exome AF: 0.427

Gnomad4 EAS exome AF: 0.399

Gnomad4 SAS exome AF: 0.403

Gnomad4 FIN exome AF: 0.439

Gnomad4 NFE exome AF: 0.413

Gnomad4 OTH exome AF: 0.402

GnomAD4 genome AF: 0.352 AC: 53580 AN: 152106 Hom.: 10443 Cov.: 33 AF XY: 0.355 AC XY: 26419 AN XY: 74334

Gnomad4 AFR AF: 0.174

Gnomad4 AMR AF: 0.456

Gnomad4 ASJ AF: 0.420

Gnomad4 EAS AF: 0.415

Gnomad4 SAS AF: 0.407

Gnomad4 FIN AF: 0.444

Gnomad4 NFE AF: 0.410

Gnomad4 OTH AF: 0.377

Alfa AF: 0.409 Hom.: 27293

Bravo AF: 0.345

Asia WGS AF: 0.448 AC: 1554 AN: 3478

EpiCase AF: 0.411

EpiControl AF: 0.412

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

KCNIP4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	4.2
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.20
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: rs3765121; hg19: chr4-20852166; COSMIC: COSV62846960;