rs17667728

Variant names:

• chr6-51648089-A-G
• rs17667728
• NM_138694.4:c.11340T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_138694.4(PKHD1):​c.11340T>C​(p.Pro3780Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0393 in 1,604,934 control chromosomes in the GnomAD database, including 1,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (123 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1282 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.577
• 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=-0.62).
• BP6: Variant 6-51648089-A-G is Benign according to our data. Variant chr6-51648089-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.577 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0365 (5552/152262) while in subpopulation AFR AF = 0.0432 (1793/41550). AF 95% confidence interval is 0.0415. There are 123 homozygotes in GnomAd4. There are 2573 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 123 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.11340T>C	p.Pro3780Pro	synonymous	Exon 63 of 67	NP_619639.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.11340T>C	p.Pro3780Pro	synonymous	Exon 63 of 67	ENSP00000360158.3	P08F94-1

Frequencies

GnomAD3 genomes AF: 0.0365 AC: 5546 AN: 152144 Hom.: 120 Cov.: 32

Gnomad AFR AF: 0.0432

Gnomad AMI AF: 0.0681

Gnomad AMR AF: 0.0238

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0222

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0426

Gnomad OTH AF: 0.0306

GnomAD2 exomes AF: 0.0328 AC: 8236 AN: 251050 AF XY: 0.0330

Gnomad AFR exome AF: 0.0437

Gnomad AMR exome AF: 0.0323

Gnomad ASJ exome AF: 0.0403

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0140

Gnomad NFE exome AF: 0.0421

Gnomad OTH exome AF: 0.0361

GnomAD4 exome AF: 0.0396 AC: 57460 AN: 1452672 Hom.: 1282 Cov.: 27 AF XY: 0.0392 AC XY: 28369 AN XY: 723266

African (AFR) AF: 0.0401 AC: 1336 AN: 33316

American (AMR) AF: 0.0327 AC: 1463 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0376 AC: 980 AN: 26064

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39664

South Asian (SAS) AF: 0.0238 AC: 2050 AN: 86108

European-Finnish (FIN) AF: 0.0167 AC: 892 AN: 53408

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5750

European-Non Finnish (NFE) AF: 0.0439 AC: 48463 AN: 1103516

Other (OTH) AF: 0.0361 AC: 2173 AN: 60134

GnomAD4 genome AF: 0.0365 AC: 5552 AN: 152262 Hom.: 123 Cov.: 32 AF XY: 0.0346 AC XY: 2573 AN XY: 74442

African (AFR) AF: 0.0432 AC: 1793 AN: 41550

American (AMR) AF: 0.0240 AC: 367 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 125 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5178

South Asian (SAS) AF: 0.0218 AC: 105 AN: 4826

European-Finnish (FIN) AF: 0.0124 AC: 132 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0426 AC: 2896 AN: 68016

Other (OTH) AF: 0.0303 AC: 64 AN: 2112

Alfa AF: 0.0413 Hom.: 84

Bravo AF: 0.0372

Asia WGS AF: 0.0130 AC: 46 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Autosomal recessive polycystic kidney disease (5)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.41
DANN	Benign	0.56
PhyloP100		-0.58
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: rs17667728; hg19: chr6-51512887;