rs116156469

Variant names:

• chr6-51912514-G-A
• rs116156469
• NM_138694.4:c.6184C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_138694.4(PKHD1):​c.6184C>T​(p.Leu2062Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000697 in 1,613,288 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2062L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0026 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (7 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.118
• Publications: 3 publications found

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

PKHD1 Gene-Disease associations (from GenCC):

• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 6-51912514-G-A is Benign according to our data. Variant chr6-51912514-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.118 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138694.4. 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
	PKHD1	NM_138694.4	MANE Select	c.6184C>T	p.Leu2062Leu	synonymous	Exon 38 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.6184C>T	p.Leu2062Leu	synonymous	Exon 38 of 61	NP_733842.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.6184C>T	p.Leu2062Leu	synonymous	Exon 38 of 67	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.6184C>T	p.Leu2062Leu	synonymous	Exon 38 of 61	ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.00256 AC: 390 AN: 152082 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00129 AC: 324 AN: 251120 AF XY: 0.00119

Gnomad AFR exome AF: 0.00978

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000498 AC: 727 AN: 1461088 Hom.: 7 Cov.: 31 AF XY: 0.000510 AC XY: 371 AN XY: 726902

African (AFR) AF: 0.00816 AC: 273 AN: 33438

American (AMR) AF: 0.000627 AC: 28 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00502 AC: 131 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00183 AC: 158 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.0000720 AC: 80 AN: 1111420

Other (OTH) AF: 0.000928 AC: 56 AN: 60350

GnomAD4 genome AF: 0.00261 AC: 397 AN: 152200 Hom.: 4 Cov.: 32 AF XY: 0.00227 AC XY: 169 AN XY: 74420

African (AFR) AF: 0.00859 AC: 357 AN: 41552

American (AMR) AF: 0.000720 AC: 11 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67992

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00142 Hom.: 0

Bravo AF: 0.00303

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Autosomal recessive polycystic kidney disease (2)
-	-	2	not provided (2)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.25
DANN	Benign	0.47
PhyloP100		-0.12
Mutation Taster		=98/2	polymorphism

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: rs116156469; hg19: chr6-51777312; COSMIC: COSV61900036;