rs972113626

Variant names:

• chr16-2135476-G-A
• rs972113626
• NM_001009944.3:c.214C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2135476-G-A
• chr16-2135476-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):​c.214C>T​(p.Leu72Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000979 in 1,168,464 control chromosomes in the GnomAD database, including 17 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (12 hom., cov: 31)
  • Exomes 𝑓: 0.00044 (5 hom.)
• Consequence: PKD1 NM_001009944.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001990
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.31
• Publications: 1 publications found

Genes affected

PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

PKD1 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-2135476-G-A is Benign according to our data. Variant chr16-2135476-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 433938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.31 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00461 (700/151706) while in subpopulation AFR AF = 0.0162 (672/41486). AF 95% confidence interval is 0.0152. There are 12 homozygotes in GnomAd4. There are 321 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009944.3. 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
	PKD1	NM_001009944.3	MANE Select	c.214C>T	p.Leu72Leu	splice_region synonymous	Exon 1 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.214C>T	p.Leu72Leu	splice_region synonymous	Exon 1 of 46	NP_000287.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.214C>T	p.Leu72Leu	splice_region synonymous	Exon 1 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.214C>T	p.Leu72Leu	splice_region synonymous	Exon 1 of 46	ENSP00000399501.1	P98161-3

Frequencies

GnomAD3 genomes AF: 0.00462 AC: 700 AN: 151598 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000985

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: 0.0000443

Gnomad OTH AF: 0.00480

GnomAD4 exome AF: 0.000437 AC: 444 AN: 1016758 Hom.: 5 Cov.: 20 AF XY: 0.000399 AC XY: 191 AN XY: 478820

African (AFR) AF: 0.0195 AC: 403 AN: 20718

American (AMR) AF: 0.00154 AC: 10 AN: 6506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11840

East Asian (EAS) AF: 0.00 AC: 0 AN: 21648

South Asian (SAS) AF: 0.00 AC: 0 AN: 18682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2582

European-Non Finnish (NFE) AF: 0.00000228 AC: 2 AN: 876954

Other (OTH) AF: 0.000738 AC: 29 AN: 39294

GnomAD4 genome AF: 0.00461 AC: 700 AN: 151706 Hom.: 12 Cov.: 31 AF XY: 0.00433 AC XY: 321 AN XY: 74156

African (AFR) AF: 0.0162 AC: 672 AN: 41486

American (AMR) AF: 0.000983 AC: 15 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67772

Other (OTH) AF: 0.00475 AC: 10 AN: 2104

Alfa AF: 0.00520 Hom.: 1

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Kidney failure (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	12
DANN	Benign	0.83
PhyloP100		2.3
PromoterAI		0.023	Neutral
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.080
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

Other links and lift over

dbSNP: rs972113626; hg19: chr16-2185477;