NM_138694.4:c.1964+17G>T

Variant names:

• chr6-52054021-C-A
• rs201349527
• NM_138694.4:c.1964+17G>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_138694.4(PKHD1):​c.1964+17G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00683 in 1,613,548 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0052 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (60 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.241

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 -8 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 6-52054021-C-A is Benign according to our data. Variant chr6-52054021-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96382.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}. Variant chr6-52054021-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00523 (796/152264) while in subpopulation NFE AF= 0.00884 (601/68014). AF 95% confidence interval is 0.00825. There are 2 homozygotes in gnomad4. There are 388 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.1964+17G>T		intron_variant	Intron 20 of 66	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.1964+17G>T		intron_variant	Intron 20 of 66	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.1964+17G>T		intron_variant	Intron 20 of 60	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.00524 AC: 797 AN: 152146 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00643

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00884

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00559 AC: 1402 AN: 250830 Hom.: 5 AF XY: 0.00612 AC XY: 830 AN XY: 135568

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00894

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00725

Gnomad FIN exome AF: 0.00536

Gnomad NFE exome AF: 0.00793

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00700 AC: 10224 AN: 1461284 Hom.: 60 Cov.: 31 AF XY: 0.00717 AC XY: 5209 AN XY: 726974

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00831

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00728

Gnomad4 FIN exome AF: 0.00562

Gnomad4 NFE exome AF: 0.00772

Gnomad4 OTH exome AF: 0.00623

GnomAD4 genome AF: 0.00523 AC: 796 AN: 152264 Hom.: 2 Cov.: 32 AF XY: 0.00521 AC XY: 388 AN XY: 74452

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00644

Gnomad4 FIN AF: 0.00574

Gnomad4 NFE AF: 0.00884

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00658 Hom.: 1

Bravo AF: 0.00412

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Aug 01, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PKHD1 c.1964+17G>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on the canonical splice donor site, but 4/5 splice prediction tools predict the gain of cryptic splice donor sites. ESEfinder predicts a gain of a binding motif for splicing enhancer SRp55. However, these predictions have yet to be confirmed by functional studies. This variant was found in 674/121292 control chromosomes (4 homozygotes), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0074681 (497/66550). This frequency is about 1.1 times the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711), suggesting this intronic variant may be a benign polymorphism found primarily in the non-Finnish Europeans. This variant was reported in at least one ARPKD patient without strong evidence for causality (Obeidova_BMC medical genetics_2015). In addition, one clinical diagnostic laboratory classified this variant as benign, without providing evidence to independently evaluate. Because of the limited clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS)-possibly benign until additional information becomes available. -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKHD1: BS2 -

not specified Benign:1

Jun 14, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive polycystic kidney disease Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PKHD1-related disorder Benign:1

Aug 30, 2021

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Uncertain	24
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.79		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201349527; hg19: chr6-51918819; COSMIC: COSV61886482;