rs73435705

chr6-52056816-A-Gchr6-52056816-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_138694.4(PKHD1):c.1603-28T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,595,814 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (15 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0150

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-52056816-A-G is Benign according to our data. Variant chr6-52056816-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 262389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00772 (1176/152284) while in subpopulation AFR AF= 0.0271 (1127/41550). AF 95% confidence interval is 0.0258. There are 17 homozygotes in gnomad4. There are 546 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.1603-28T>C		intron_variant		ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.1603-28T>C		intron_variant		1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.1603-28T>C		intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.00772 AC: 1174 AN: 152166 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00192 AC: 481 AN: 250912 Hom.: 5 AF XY: 0.00142 AC XY: 192 AN XY: 135646

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000872 AC: 1259 AN: 1443530 Hom.: 15 Cov.: 26 AF XY: 0.000772 AC XY: 555 AN XY: 719378

Gnomad4 AFR exome AF: 0.0291

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000721

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00772 AC: 1176 AN: 152284 Hom.: 17 Cov.: 32 AF XY: 0.00733 AC XY: 546 AN XY: 74474

Gnomad4 AFR AF: 0.0271

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00142 Hom.: 0

Bravo AF: 0.00894

Asia WGS AF: 0.00202 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autosomal recessive polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 14, 2018

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	2.2
Dann	Benign	0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs73435705; hg19: chr6-51921614;