chr6-52026054-C-G

Variant names:

• chr6-52026054-C-G
• rs9689306
• NM_138694.4:c.3756G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_138694.4(PKHD1):​c.3756G>C​(p.Leu1252Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.052 in 1,613,986 control chromosomes in the GnomAD database, including 2,565 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1252L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.038 (120 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2445 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -5.76
• Publications: 7 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: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-52026054-C-G is Benign according to our data. Variant chr6-52026054-C-G is described in ClinVar as Benign. ClinVar VariationId is 167488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.76 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

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.3756G>C	p.Leu1252Leu	synonymous	Exon 32 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.3756G>C	p.Leu1252Leu	synonymous	Exon 32 of 61	NP_733842.2	P08F94-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.3756G>C	p.Leu1252Leu	synonymous	Exon 32 of 67	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.3756G>C	p.Leu1252Leu	synonymous	Exon 32 of 61	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.0378 AC: 5746 AN: 152140 Hom.: 120 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.0238

Gnomad ASJ AF: 0.0908

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.0383

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0589

Gnomad OTH AF: 0.0388

GnomAD2 exomes AF: 0.0377 AC: 9460 AN: 250624 AF XY: 0.0379

Gnomad AFR exome AF: 0.00958

Gnomad AMR exome AF: 0.0210

Gnomad ASJ exome AF: 0.0924

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0401

Gnomad NFE exome AF: 0.0547

Gnomad OTH exome AF: 0.0521

GnomAD4 exome AF: 0.0534 AC: 78117 AN: 1461728 Hom.: 2445 Cov.: 37 AF XY: 0.0520 AC XY: 37844 AN XY: 727168

African (AFR) AF: 0.00818 AC: 274 AN: 33480

American (AMR) AF: 0.0218 AC: 977 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0897 AC: 2344 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00824 AC: 711 AN: 86256

European-Finnish (FIN) AF: 0.0436 AC: 2325 AN: 53380

Middle Eastern (MID) AF: 0.0114 AC: 66 AN: 5768

European-Non Finnish (NFE) AF: 0.0615 AC: 68434 AN: 1111896

Other (OTH) AF: 0.0494 AC: 2985 AN: 60390

GnomAD4 genome AF: 0.0377 AC: 5744 AN: 152258 Hom.: 120 Cov.: 32 AF XY: 0.0359 AC XY: 2671 AN XY: 74434

African (AFR) AF: 0.0104 AC: 433 AN: 41550

American (AMR) AF: 0.0237 AC: 363 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0908 AC: 315 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00808 AC: 39 AN: 4824

European-Finnish (FIN) AF: 0.0383 AC: 406 AN: 10606

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0589 AC: 4003 AN: 68018

Other (OTH) AF: 0.0384 AC: 81 AN: 2112

Alfa AF: 0.0566 Hom.: 91

Bravo AF: 0.0361

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Autosomal recessive polycystic kidney disease (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.016
DANN	Benign	0.39
PhyloP100		-5.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9689306; hg19: chr6-51890852; COSMIC: COSV61863181;