rs886038726

Variant names:

• chr6-52066086-G-A
• rs886038726
• NM_138694.4:c.779-9C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_138694.4(PKHD1):​c.779-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000041 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKHD1 NM_138694.4 intron
• Scores: Splicing: ADA: 0.00002739
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0870
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 6-52066086-G-A is Benign according to our data. Variant chr6-52066086-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 262414.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.779-9C>T		intron_variant	Intron 11 of 66	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.779-9C>T		intron_variant	Intron 11 of 66	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.779-9C>T		intron_variant	Intron 11 of 60	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.0000409 AC: 3 AN: 73436 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000369

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000311

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000326

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000403 AC: 7 AN: 173538 AF XY: 0.0000635

Gnomad AFR exome AF: 0.0000808

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000643

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000225 AC: 21 AN: 933546 Hom.: 0 Cov.: 18 AF XY: 0.0000227 AC XY: 11 AN XY: 484284

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000220 AC: 5 AN: 22774

American (AMR) AF: 0.000105 AC: 4 AN: 38226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21724

East Asian (EAS) AF: 0.00 AC: 0 AN: 35264

South Asian (SAS) AF: 0.00 AC: 0 AN: 71020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4516

European-Non Finnish (NFE) AF: 0.0000154 AC: 10 AN: 650760

Other (OTH) AF: 0.0000476 AC: 2 AN: 42046

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000409 AC: 3 AN: 73436 Hom.: 0 Cov.: 29 AF XY: 0.0000286 AC XY: 1 AN XY: 34988

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000369 AC: 1 AN: 27116

American (AMR) AF: 0.00 AC: 0 AN: 4972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1668

East Asian (EAS) AF: 0.00 AC: 0 AN: 1974

South Asian (SAS) AF: 0.00 AC: 0 AN: 2184

European-Finnish (FIN) AF: 0.000311 AC: 1 AN: 3212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 148

European-Non Finnish (NFE) AF: 0.0000326 AC: 1 AN: 30712

Other (OTH) AF: 0.00 AC: 0 AN: 894

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely 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	7.4
DANN	Benign	0.47
PhyloP100		-0.087

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.018
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: rs886038726; hg19: chr6-51930884;