NM_001300921.2:c.974T>C

Variant names:

• chr5-137906433-T-C
• rs1350218153
• NM_001300921.2:c.974T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001300921.2(PKD2L2):​c.974T>C​(p.Leu325Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000263 in 1,523,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: PKD2L2 NM_001300921.2 missense, splice_region
• Scores: Splicing: ADA: 0.1002
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.528
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2L2	NM_001300921.2	MANE Select	c.974T>C	p.Leu325Pro	missense splice_region	Exon 6 of 15	NP_001287850.1	Q9NZM6-1
	PKD2L2	NM_014386.4		c.974T>C	p.Leu325Pro	missense splice_region	Exon 6 of 14	NP_055201.2	Q9NZM6-5
	PKD2L2	NM_001258448.2		c.974T>C	p.Leu325Pro	missense splice_region	Exon 6 of 15	NP_001245377.1	Q9NZM6-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2L2	ENST00000508883.6	TSL:1 MANE Select	c.974T>C	p.Leu325Pro	missense splice_region	Exon 6 of 15	ENSP00000424725.1	Q9NZM6-1
	PKD2L2	ENST00000290431.5	TSL:1	c.974T>C	p.Leu325Pro	missense splice_region	Exon 6 of 14	ENSP00000290431.5	Q9NZM6-5
	PKD2L2	ENST00000508638.5	TSL:1	c.974T>C	p.Leu325Pro	missense splice_region	Exon 6 of 13	ENSP00000423382.1	Q9NZM6-6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000219 AC: 3 AN: 1371248 Hom.: 0 Cov.: 22 AF XY: 0.00000291 AC XY: 2 AN XY: 687314

African (AFR) AF: 0.0000317 AC: 1 AN: 31500

American (AMR) AF: 0.00 AC: 0 AN: 43842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25238

East Asian (EAS) AF: 0.00 AC: 0 AN: 39200

South Asian (SAS) AF: 0.00 AC: 0 AN: 83244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5438

European-Non Finnish (NFE) AF: 0.00000194 AC: 2 AN: 1033592

Other (OTH) AF: 0.00 AC: 0 AN: 57188

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74386

African (AFR) AF: 0.00 AC: 0 AN: 41482

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	0.099
Eigen_PC	Benign	0.054
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.53
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.054	T
Polyphen		0.87	P
Vest4		0.65
MutPred		0.71		Loss of stability (P = 0.0145)
MVP		0.83
MPC		0.61
ClinPred		0.97	D
GERP RS		3.0
Varity_R		0.91
gMVP		0.80
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.10
dbscSNV1_RF	Benign	0.17
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: rs1350218153; hg19: chr5-137242122;