NM_138694.4:c.7764A>G

Variant names:

• chr6-51856040-T-C
• rs9349603
• NM_138694.4:c.7764A>G

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.7764A>G​(p.Leu2588Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 1,592,754 control chromosomes in the GnomAD database, including 114,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13518 hom., cov: 33)
  • Exomes 𝑓: 0.35 (100668 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.84
• Publications: 19 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=-0.58).
• BP6: Variant 6-51856040-T-C is Benign according to our data. Variant chr6-51856040-T-C is described in ClinVar as Benign. ClinVar VariationId is 96423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.84 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.83 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.7764A>G	p.Leu2588Leu	synonymous	Exon 49 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.7764A>G	p.Leu2588Leu	synonymous	Exon 49 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.7764A>G	p.Leu2588Leu	synonymous	Exon 49 of 67	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.7764A>G	p.Leu2588Leu	synonymous	Exon 49 of 61	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.402 AC: 61172 AN: 152014 Hom.: 13509 Cov.: 33

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.851

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.370

GnomAD2 exomes AF: 0.445 AC: 111895 AN: 251352 AF XY: 0.436

Gnomad AFR exome AF: 0.433

Gnomad AMR exome AF: 0.654

Gnomad ASJ exome AF: 0.253

Gnomad EAS exome AF: 0.868

Gnomad FIN exome AF: 0.451

Gnomad NFE exome AF: 0.315

Gnomad OTH exome AF: 0.373

GnomAD4 exome AF: 0.352 AC: 507784 AN: 1440622 Hom.: 100668 Cov.: 30 AF XY: 0.356 AC XY: 255636 AN XY: 717842

African (AFR) AF: 0.417 AC: 13719 AN: 32924

American (AMR) AF: 0.634 AC: 28350 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 6519 AN: 26020

East Asian (EAS) AF: 0.828 AC: 32697 AN: 39512

South Asian (SAS) AF: 0.513 AC: 43939 AN: 85636

European-Finnish (FIN) AF: 0.436 AC: 23297 AN: 53416

Middle Eastern (MID) AF: 0.267 AC: 1533 AN: 5736

European-Non Finnish (NFE) AF: 0.308 AC: 336157 AN: 1092980

Other (OTH) AF: 0.361 AC: 21573 AN: 59706

GnomAD4 genome AF: 0.402 AC: 61212 AN: 152132 Hom.: 13518 Cov.: 33 AF XY: 0.417 AC XY: 31031 AN XY: 74372

African (AFR) AF: 0.431 AC: 17882 AN: 41492

American (AMR) AF: 0.531 AC: 8124 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 902 AN: 3470

East Asian (EAS) AF: 0.851 AC: 4403 AN: 5172

South Asian (SAS) AF: 0.539 AC: 2601 AN: 4826

European-Finnish (FIN) AF: 0.452 AC: 4783 AN: 10584

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.317 AC: 21550 AN: 67986

Other (OTH) AF: 0.368 AC: 777 AN: 2110

Alfa AF: 0.343 Hom.: 14896

Bravo AF: 0.407

Asia WGS AF: 0.624 AC: 2168 AN: 3478

EpiCase AF: 0.307

EpiControl AF: 0.311

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal recessive polycystic kidney disease (3)
-	-	2	not specified (2)
-	-	2	Polycystic kidney disease 4 (2)
-	-	1	not provided (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.4
DANN	Benign	0.72
PhyloP100		1.8
Mutation Taster		=99/1	polymorphism (auto)

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: rs9349603; hg19: chr6-51720838; COSMIC: COSV61896972;