6-51627068-A-T

Variant names:

• chr6-51627068-A-T
• rs2661488
• NM_138694.4:c.11714T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138694.4(PKHD1):​c.11714T>A​(p.Ile3905Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0291 in 1,610,104 control chromosomes in the GnomAD database, including 975 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (233 hom., cov: 32)
  • Exomes 𝑓: 0.028 (742 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0420
• Publications: 19 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: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019351542).
• BP6: Variant 6-51627068-A-T is Benign according to our data. Variant chr6-51627068-A-T is described in ClinVar as [Benign]. Clinvar id is 96373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0901 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.11714T>A	p.Ile3905Asn	missense_variant	Exon 66 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.11714T>A	p.Ile3905Asn	missense_variant	Exon 66 of 67	1	NM_138694.4	ENSP00000360158.3

Frequencies

GnomAD3 genomes AF: 0.0426 AC: 6482 AN: 151986 Hom.: 232 Cov.: 32

Gnomad AFR AF: 0.0927

Gnomad AMI AF: 0.0670

Gnomad AMR AF: 0.0251

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0268

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0273 AC: 6872 AN: 251262 AF XY: 0.0263

Gnomad AFR exome AF: 0.0943

Gnomad AMR exome AF: 0.0293

Gnomad ASJ exome AF: 0.0288

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.0268

Gnomad OTH exome AF: 0.0219

GnomAD4 exome AF: 0.0277 AC: 40341 AN: 1458000 Hom.: 742 Cov.: 29 AF XY: 0.0271 AC XY: 19664 AN XY: 725572

African (AFR) AF: 0.0956 AC: 3186 AN: 33330

American (AMR) AF: 0.0292 AC: 1306 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.0275 AC: 719 AN: 26104

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39674

South Asian (SAS) AF: 0.0203 AC: 1748 AN: 86178

European-Finnish (FIN) AF: 0.0138 AC: 737 AN: 53414

Middle Eastern (MID) AF: 0.0161 AC: 93 AN: 5762

European-Non Finnish (NFE) AF: 0.0279 AC: 30953 AN: 1108592

Other (OTH) AF: 0.0265 AC: 1595 AN: 60268

GnomAD4 genome AF: 0.0427 AC: 6492 AN: 152104 Hom.: 233 Cov.: 32 AF XY: 0.0412 AC XY: 3065 AN XY: 74354

African (AFR) AF: 0.0926 AC: 3840 AN: 41480

American (AMR) AF: 0.0252 AC: 385 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 84 AN: 3468

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5176

South Asian (SAS) AF: 0.0197 AC: 95 AN: 4820

European-Finnish (FIN) AF: 0.0105 AC: 111 AN: 10586

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0268 AC: 1824 AN: 67994

Other (OTH) AF: 0.0374 AC: 79 AN: 2112

Alfa AF: 0.0281 Hom.: 54

Bravo AF: 0.0470

TwinsUK AF: 0.0291 AC: 108

ALSPAC AF: 0.0340 AC: 131

ESP6500AA AF: 0.0921 AC: 406

ESP6500EA AF: 0.0253 AC: 218

ExAC AF: 0.0286 AC: 3475

Asia WGS AF: 0.0180 AC: 62 AN: 3478

EpiCase AF: 0.0277

EpiControl AF: 0.0270

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

Jan 29, 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

- -

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 PKHD1 p.Ile3905Asn variant was identified in dbSNP (ID: rs2661488) “With other allele” and in control databases in 7988 of 276978 chromosomes (184 homozygous) at a frequency of 0.03 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 2274 (102 homozygous) of 24016 chromosomes (freq: 0.09), Other in 143 of 6456 chromosomes (freq: 0.02), Latino in 1011 (17 homozygous) of 34356 chromosomes (freq: 0.03), European Non-Finnish in 3354 (43 homozygous) of 126578 chromosomes (freq: 0.03), Ashkenazi Jewish in 285 (5 homozygous) of 10144 chromosomes (freq: 0.03), East Asian in 7 of 18856 chromosomes (freq: 0.0004), European Finnish in 299 (3 homozygous) of 25790 chromosomes (freq: 0.01), and South Asian in 615 (14 homozygous) of 30782 chromosomes (freq: 0.02). The p.Ile3905Asn residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory criteria to be classified as benign. -

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
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.13
DANN	Benign	0.44
DEOGEN2	Benign	0.070	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.00044	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-2.2	N
PhyloP100		0.042
PrimateAI	Benign	0.41	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	0.80	T
Polyphen		0.0	B
Vest4		0.039
MPC		0.10
ClinPred		0.0034	T
GERP RS		-1.6
Varity_R		0.046
gMVP		0.043
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: rs2661488; hg19: chr6-51491866; COSMIC: COSV64392624;