rs547420704

Variant names:

• chr6-52024539-TAAAG-T
• rs547420704
• NM_138694.4:c.5236+31_5236+34delCTTT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_138694.4(PKHD1):​c.5236+31_5236+34delCTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00638 in 1,590,448 control chromosomes in the GnomAD database, including 53 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0043 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (52 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.464
• 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.

• BP6: Variant 6-52024539-TAAAG-T is Benign according to our data. Variant chr6-52024539-TAAAG-T is described in ClinVar as Likely_benign. ClinVar VariationId is 262405.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 52 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.5236+31_5236+34delCTTT		intron_variant	Intron 32 of 66	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.5236+31_5236+34delCTTT		intron_variant	Intron 32 of 66	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.5236+31_5236+34delCTTT		intron_variant	Intron 32 of 60	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.00428 AC: 652 AN: 152228 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00772

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00661

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00445 AC: 1096 AN: 246460 AF XY: 0.00440

Gnomad AFR exome AF: 0.00133

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00501

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00729

Gnomad NFE exome AF: 0.00693

Gnomad OTH exome AF: 0.00597

GnomAD4 exome AF: 0.00661 AC: 9503 AN: 1438102 Hom.: 52 AF XY: 0.00635 AC XY: 4551 AN XY: 716966

African (AFR) AF: 0.00109 AC: 36 AN: 33056

American (AMR) AF: 0.00145 AC: 65 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00462 AC: 120 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.000899 AC: 77 AN: 85660

European-Finnish (FIN) AF: 0.00733 AC: 383 AN: 52274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00776 AC: 8467 AN: 1091472

Other (OTH) AF: 0.00595 AC: 355 AN: 59646

GnomAD4 genome AF: 0.00428 AC: 652 AN: 152346 Hom.: 1 Cov.: 32 AF XY: 0.00391 AC XY: 291 AN XY: 74498

African (AFR) AF: 0.00156 AC: 65 AN: 41578

American (AMR) AF: 0.00229 AC: 35 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00772 AC: 82 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00661 AC: 450 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00476 Hom.: 0

Bravo AF: 0.00352

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

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

- -

Polycystic kidney disease 4 Benign:1

Oct 13, 2017

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.46
Mutation Taster		=100/0	polymorphism

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: rs547420704; hg19: chr6-51889337;