6-52053170-T-G

Variant names:

• chr6-52053170-T-G
• rs4715271
• NM_138694.4:c.2046A>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.2046A>C​(p.Pro682Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0974 in 1,614,084 control chromosomes in the GnomAD database, including 8,321 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. P682P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.078 (574 hom., cov: 32)
  • Exomes 𝑓: 0.099 (7747 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -5.03
• Publications: 12 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=-0.92).
• BP6: Variant 6-52053170-T-G is Benign according to our data. Variant chr6-52053170-T-G is described in ClinVar as Benign. ClinVar VariationId is 96384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.102 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.2046A>C	p.Pro682Pro	synonymous	Exon 21 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.2046A>C	p.Pro682Pro	synonymous	Exon 21 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.2046A>C	p.Pro682Pro	synonymous	Exon 21 of 67	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.2046A>C	p.Pro682Pro	synonymous	Exon 21 of 61	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.0776 AC: 11811 AN: 152176 Hom.: 570 Cov.: 32

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.0812

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.0392

Gnomad SAS AF: 0.0684

Gnomad FIN AF: 0.0690

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.102

GnomAD2 exomes AF: 0.0874 AC: 21964 AN: 251214 AF XY: 0.0898

Gnomad AFR exome AF: 0.0298

Gnomad AMR exome AF: 0.0672

Gnomad ASJ exome AF: 0.155

Gnomad EAS exome AF: 0.0446

Gnomad FIN exome AF: 0.0743

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.0986

GnomAD4 exome AF: 0.0995 AC: 145440 AN: 1461790 Hom.: 7747 Cov.: 33 AF XY: 0.0996 AC XY: 72447 AN XY: 727196

African (AFR) AF: 0.0324 AC: 1086 AN: 33480

American (AMR) AF: 0.0696 AC: 3111 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 4106 AN: 26136

East Asian (EAS) AF: 0.0466 AC: 1850 AN: 39696

South Asian (SAS) AF: 0.0801 AC: 6905 AN: 86258

European-Finnish (FIN) AF: 0.0732 AC: 3911 AN: 53414

Middle Eastern (MID) AF: 0.160 AC: 920 AN: 5768

European-Non Finnish (NFE) AF: 0.106 AC: 117657 AN: 1111922

Other (OTH) AF: 0.0976 AC: 5894 AN: 60392

GnomAD4 genome AF: 0.0777 AC: 11828 AN: 152294 Hom.: 574 Cov.: 32 AF XY: 0.0768 AC XY: 5723 AN XY: 74470

African (AFR) AF: 0.0329 AC: 1366 AN: 41570

American (AMR) AF: 0.0811 AC: 1242 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 530 AN: 3470

East Asian (EAS) AF: 0.0393 AC: 204 AN: 5186

South Asian (SAS) AF: 0.0685 AC: 330 AN: 4820

European-Finnish (FIN) AF: 0.0690 AC: 732 AN: 10606

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7080 AN: 68016

Other (OTH) AF: 0.105 AC: 223 AN: 2114

Alfa AF: 0.0787 Hom.: 271

Bravo AF: 0.0772

Asia WGS AF: 0.0580 AC: 203 AN: 3478

EpiCase AF: 0.110

EpiControl AF: 0.114

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	-0.92
CADD	Benign	0.43
DANN	Benign	0.40
PhyloP100		-5.0
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: rs4715271; hg19: chr6-51917968; COSMIC: COSV61858788;