2-95310371-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_013434.5(KCNIP3):c.32C>T(p.Ser11Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,611,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: KCNIP3 NM_013434.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04

Genes affected

KCNIP3 (HGNC:15523): (potassium voltage-gated channel interacting protein 3) This gene encodes a member of the family of voltage-gated potassium (Kv) channel-interacting proteins, which belong to the recoverin branch of the EF-hand superfamily. Members of this family are small calcium binding proteins containing EF-hand-like domains. They are integral subunit components of native Kv4 channel complexes that may regulate A-type currents, and hence neuronal excitability, in response to changes in intracellular calcium. The encoded protein also functions as a calcium-regulated transcriptional repressor, and interacts with presenilins. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04209414).
• BS2: High AC in GnomAd at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNIP3	NM_013434.5	c.32C>T	p.Ser11Leu	missense_variant	2/9	ENST00000295225.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNIP3	ENST00000295225.10	c.32C>T	p.Ser11Leu	missense_variant	2/9	1	NM_013434.5
KCNIP3	ENST00000475491.1	n.133C>T		non_coding_transcript_exon_variant	2/2	1
KCNIP3	ENST00000360990.7	n.32C>T		non_coding_transcript_exon_variant	2/9	5
KCNIP3	ENST00000377181.2	n.107+12918C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000191

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000140 AC: 35 AN: 249936 Hom.: 0 AF XY: 0.000141 AC XY: 19 AN XY: 135004

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.000302

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000207 AC: 302 AN: 1459418 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 156 AN XY: 725584

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000930

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000237

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74452

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000263 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000327

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2023

The c.32C>T (p.S11L) alteration is located in exon 2 (coding exon 2) of the KCNIP3 gene. This alteration results from a C to T substitution at nucleotide position 32, causing the serine (S) at amino acid position 11 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.049	T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.042	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.43	N;N
REVEL	Benign	0.083
Sift	Benign	0.37	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.044	B;.
Vest4		0.27
MVP		0.54
MPC		0.38
ClinPred		0.023	T
GERP RS		4.2
Varity_R		0.052
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149504046; hg19: chr2-95976119;