Genetic Variant PKD2L2:p.Leu261Val (chr5-137906240-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001300921.2(PKD2L2):c.781C>G(p.Leu261Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L261I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PKD2L2
NM_001300921.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.88

Publications

0 publications found

Variant links:

Genes affected

PKD2L2 (HGNC:9012): (polycystin 2 like 2, transient receptor potential cation channel) Predicted to enable calcium channel activity. Predicted to be involved in detection of mechanical stimulus. Predicted to be integral component of membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

PKD2L2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08877763).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001300921.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PKD2L2	NM_001300921.2	MANE Select	c.781C>G	p.Leu261Val	missense	Exon 6 of 15	NP_001287850.1	Q9NZM6-1
PKD2L2	NM_014386.4		c.781C>G	p.Leu261Val	missense	Exon 6 of 14	NP_055201.2	Q9NZM6-5
PKD2L2	NM_001258448.2		c.781C>G	p.Leu261Val	missense	Exon 6 of 15	NP_001245377.1	Q9NZM6-7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PKD2L2	ENST00000508883.6	TSL:1 MANE Select	c.781C>G	p.Leu261Val	missense	Exon 6 of 15	ENSP00000424725.1	Q9NZM6-1
PKD2L2	ENST00000290431.5	TSL:1	c.781C>G	p.Leu261Val	missense	Exon 6 of 14	ENSP00000290431.5	Q9NZM6-5
PKD2L2	ENST00000508638.5	TSL:1	c.781C>G	p.Leu261Val	missense	Exon 6 of 13	ENSP00000423382.1	Q9NZM6-6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1458854

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725598

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33374

American (AMR)

AF:

0.00

AC:

AN:

44442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26080

East Asian (EAS)

AF:

0.00

AC:

AN:

39614

South Asian (SAS)

AF:

0.00

AC:

AN:

85568

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110338

Other (OTH)

AF:

0.00

AC:

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.4

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.089

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.65

M_CAP

Benign

0.020

MetaRNN

Benign

0.089

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.72

PhyloP100

-1.9

PrimateAI

Benign

0.40

PROVEAN

Benign

0.020

REVEL

Benign

0.081

Sift

Benign

0.37

Sift4G

Benign

0.17

Polyphen

0.0010

Vest4

0.23

MutPred

0.52

Gain of catalytic residue at L261 (P = 0.0487)

MVP

0.47

MPC

0.20

ClinPred

0.10

GERP RS

-0.087

Varity_R

0.054

gMVP

0.35

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over