rs12352254

Variant names:

• chr9-2729686-C-G
• rs12352254
• NM_133497.4:c.1597C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133497.4(KCNV2):​c.1597C>G​(p.Leu533Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0858 in 1,613,502 control chromosomes in the GnomAD database, including 9,048 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2708 hom., cov: 32)
  • Exomes 𝑓: 0.079 (6340 hom.)
• Consequence: KCNV2 NM_133497.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.122
• Publications: 15 publications found

Genes affected

KCNV2 (HGNC:19698): (potassium voltage-gated channel modifier subfamily V member 2) 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. This gene encodes a member of the potassium voltage-gated channel subfamily V. This member is identified as a 'silent subunit', and it does not form homomultimers, but forms heteromultimers with several other subfamily members. Through obligatory heteromerization, it exerts a function-altering effect on other potassium channel subunits. This protein is strongly expressed in pancreas and has a weaker expression in several other tissues. [provided by RefSeq, Jul 2008]

PUM3 (HGNC:29676): (pumilio RNA binding family member 3) Enables RNA binding activity. Involved in regulation of protein ADP-ribosylation. Located in chromosome; endoplasmic reticulum; and nuclear lumen. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000286670 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004412204).
• BP6: Variant 9-2729686-C-G is Benign according to our data. Variant chr9-2729686-C-G is described in ClinVar as Benign. ClinVar VariationId is 262361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133497.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNV2	NM_133497.4	MANE Select	c.1597C>G	p.Leu533Val	missense	Exon 2 of 2	NP_598004.1	Q8TDN2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNV2	ENST00000382082.4	TSL:1 MANE Select	c.1597C>G	p.Leu533Val	missense	Exon 2 of 2	ENSP00000371514.3	Q8TDN2
	PUM3	ENST00000490444.2	TSL:5	n.*127-9154G>C		intron	N/A	ENSP00000474467.1	S4R3K8
	ENSG00000286670	ENST00000768783.1		n.113+16612G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22397 AN: 151938 Hom.: 2689 Cov.: 32

Gnomad AFR AF: 0.330

Gnomad AMI AF: 0.0846

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.0890

Gnomad EAS AF: 0.0251

Gnomad SAS AF: 0.0479

Gnomad FIN AF: 0.0705

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0745

Gnomad OTH AF: 0.118

GnomAD2 exomes AF: 0.0957 AC: 24048 AN: 251276 AF XY: 0.0858

Gnomad AFR exome AF: 0.340

Gnomad AMR exome AF: 0.155

Gnomad ASJ exome AF: 0.0881

Gnomad EAS exome AF: 0.0250

Gnomad FIN exome AF: 0.0743

Gnomad NFE exome AF: 0.0728

Gnomad OTH exome AF: 0.0805

GnomAD4 exome AF: 0.0793 AC: 115941 AN: 1461446 Hom.: 6340 Cov.: 32 AF XY: 0.0768 AC XY: 55833 AN XY: 727074

African (AFR) AF: 0.346 AC: 11572 AN: 33448

American (AMR) AF: 0.150 AC: 6718 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0857 AC: 2239 AN: 26130

East Asian (EAS) AF: 0.0234 AC: 928 AN: 39696

South Asian (SAS) AF: 0.0469 AC: 4044 AN: 86246

European-Finnish (FIN) AF: 0.0768 AC: 4101 AN: 53414

Middle Eastern (MID) AF: 0.0409 AC: 236 AN: 5766

European-Non Finnish (NFE) AF: 0.0727 AC: 80842 AN: 1111644

Other (OTH) AF: 0.0871 AC: 5261 AN: 60382

GnomAD4 genome AF: 0.148 AC: 22466 AN: 152056 Hom.: 2708 Cov.: 32 AF XY: 0.144 AC XY: 10691 AN XY: 74302

African (AFR) AF: 0.331 AC: 13719 AN: 41448

American (AMR) AF: 0.127 AC: 1937 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0890 AC: 309 AN: 3472

East Asian (EAS) AF: 0.0250 AC: 129 AN: 5170

South Asian (SAS) AF: 0.0475 AC: 229 AN: 4816

European-Finnish (FIN) AF: 0.0705 AC: 746 AN: 10580

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0745 AC: 5068 AN: 67988

Other (OTH) AF: 0.116 AC: 244 AN: 2112

Alfa AF: 0.0833 Hom.: 550

Bravo AF: 0.162

TwinsUK AF: 0.0666 AC: 247

ALSPAC AF: 0.0765 AC: 295

ESP6500AA AF: 0.321 AC: 1413

ESP6500EA AF: 0.0745 AC: 641

ExAC AF: 0.0992 AC: 12039

Asia WGS AF: 0.0650 AC: 227 AN: 3478

EpiCase AF: 0.0703

EpiControl AF: 0.0641

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cone dystrophy with supernormal rod response (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	8.6
DANN	Benign	0.71
DEOGEN2	Benign	0.047	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0088	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.12
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.20
Sift	Benign	0.98	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.017
MPC		0.017
ClinPred		0.0010	T
GERP RS		0.058
Varity_R		0.036
gMVP		0.47
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12352254; hg19: chr9-2729686; COSMIC: COSV66056058;