rs6901799

Variant names:

• chr6-52082459-G-A
• rs6901799
• NM_138694.4:c.214C>T

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.214C>T​(p.Leu72Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,613,794 control chromosomes in the GnomAD database, including 9,096 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. L72L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.093 (708 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8388 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.398
• Publications: 17 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=-0.88).
• BP6: Variant 6-52082459-G-A is Benign according to our data. Variant chr6-52082459-G-A is described in ClinVar as Benign. ClinVar VariationId is 96385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.398 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.106 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.214C>T	p.Leu72Leu	synonymous	Exon 4 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.214C>T	p.Leu72Leu	synonymous	Exon 4 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.214C>T	p.Leu72Leu	synonymous	Exon 4 of 67	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.214C>T	p.Leu72Leu	synonymous	Exon 4 of 61	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.0926 AC: 14090 AN: 152098 Hom.: 701 Cov.: 32

Gnomad AFR AF: 0.0779

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.0879

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0355

Gnomad SAS AF: 0.0702

Gnomad FIN AF: 0.0692

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.117

GnomAD2 exomes AF: 0.0938 AC: 23580 AN: 251360 AF XY: 0.0954

Gnomad AFR exome AF: 0.0748

Gnomad AMR exome AF: 0.0721

Gnomad ASJ exome AF: 0.172

Gnomad EAS exome AF: 0.0417

Gnomad FIN exome AF: 0.0743

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.104 AC: 151794 AN: 1461576 Hom.: 8388 Cov.: 33 AF XY: 0.104 AC XY: 75485 AN XY: 727094

African (AFR) AF: 0.0797 AC: 2669 AN: 33476

American (AMR) AF: 0.0746 AC: 3335 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 4531 AN: 26132

East Asian (EAS) AF: 0.0441 AC: 1750 AN: 39700

South Asian (SAS) AF: 0.0829 AC: 7146 AN: 86248

European-Finnish (FIN) AF: 0.0733 AC: 3917 AN: 53420

Middle Eastern (MID) AF: 0.179 AC: 1031 AN: 5768

European-Non Finnish (NFE) AF: 0.109 AC: 121095 AN: 1111716

Other (OTH) AF: 0.105 AC: 6320 AN: 60392

GnomAD4 genome AF: 0.0928 AC: 14119 AN: 152218 Hom.: 708 Cov.: 32 AF XY: 0.0913 AC XY: 6795 AN XY: 74418

African (AFR) AF: 0.0781 AC: 3242 AN: 41536

American (AMR) AF: 0.0879 AC: 1344 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 574 AN: 3472

East Asian (EAS) AF: 0.0355 AC: 184 AN: 5178

South Asian (SAS) AF: 0.0701 AC: 337 AN: 4808

European-Finnish (FIN) AF: 0.0692 AC: 734 AN: 10604

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7324 AN: 68006

Other (OTH) AF: 0.121 AC: 255 AN: 2116

Alfa AF: 0.109 Hom.: 1822

Bravo AF: 0.0945

Asia WGS AF: 0.0640 AC: 222 AN: 3478

EpiCase AF: 0.116

EpiControl AF: 0.120

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)
-	-	1	not provided (1)
-	-	1	Polycystic kidney disease (1)
-	-	1	Polycystic kidney disease 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.85
DANN	Benign	0.46
PhyloP100		0.40
Mutation Taster		=100/0	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: rs6901799; hg19: chr6-51947257; COSMIC: COSV61858821;