chr6-52058611-A-T

Variant names:

• chr6-52058611-A-T
• rs4715272
• NM_138694.4:c.1234-10T>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138694.4(PKHD1):​c.1234-10T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,612,430 control chromosomes in the GnomAD database, including 21,690 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1506 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20184 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Scores: Splicing: ADA: 0.6013
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.570

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=-0.8).
• BP6: Variant 6-52058611-A-T is Benign according to our data. Variant chr6-52058611-A-T is described in ClinVar as [Benign]. Clinvar id is 96377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.1234-10T>A		intron_variant	Intron 15 of 66	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.1234-10T>A		intron_variant	Intron 15 of 66	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.1234-10T>A		intron_variant	Intron 15 of 60	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20580 AN: 152070 Hom.: 1496 Cov.: 32

Gnomad AFR AF: 0.0915

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.0788

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.155

GnomAD3 exomes AF: 0.148 AC: 36810 AN: 249096 Hom.: 2999 AF XY: 0.154 AC XY: 20782 AN XY: 134682

Gnomad AFR exome AF: 0.0860

Gnomad AMR exome AF: 0.0932

Gnomad ASJ exome AF: 0.196

Gnomad EAS exome AF: 0.0850

Gnomad SAS exome AF: 0.201

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.172

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.163 AC: 237313 AN: 1460242 Hom.: 20184 Cov.: 32 AF XY: 0.165 AC XY: 119631 AN XY: 726550

Gnomad4 AFR exome AF: 0.0897

Gnomad4 AMR exome AF: 0.0966

Gnomad4 ASJ exome AF: 0.197

Gnomad4 EAS exome AF: 0.0872

Gnomad4 SAS exome AF: 0.201

Gnomad4 FIN exome AF: 0.111

Gnomad4 NFE exome AF: 0.169

Gnomad4 OTH exome AF: 0.157

GnomAD4 genome AF: 0.135 AC: 20617 AN: 152188 Hom.: 1506 Cov.: 32 AF XY: 0.134 AC XY: 9981 AN XY: 74424

Gnomad4 AFR AF: 0.0917

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.0790

Gnomad4 SAS AF: 0.191

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.159

Alfa AF: 0.0942 Hom.: 174

Bravo AF: 0.134

Asia WGS AF: 0.152 AC: 532 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 11, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:2

Feb 04, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease 4 Benign:2

Jun 19, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The c.1234-10T>A, p.? variant was identified in 15% of 18201 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.3
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.60
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.020		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: rs4715272; hg19: chr6-51923409; COSMIC: COSV61858802;