chr6-51836367-C-T

Variant names:

• chr6-51836367-C-T
• rs12523900
• NM_138694.4:c.8173+37G>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.8173+37G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0511 in 1,346,820 control chromosomes in the GnomAD database, including 2,047 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (231 hom., cov: 32)
  • Exomes 𝑓: 0.051 (1816 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.454
• Publications: 6 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 (BayesDel_noAF=-0.88).
• BP6: Variant 6-51836367-C-T is Benign according to our data. Variant chr6-51836367-C-T is described in ClinVar as Benign. ClinVar VariationId is 262419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0682 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138694.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	NM_138694.4	MANE Select	c.8173+37G>A		intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.8173+37G>A		intron	N/A	NP_733842.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.8173+37G>A		intron	N/A	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.8173+37G>A		intron	N/A	ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.0537 AC: 8166 AN: 152014 Hom.: 228 Cov.: 32

Gnomad AFR AF: 0.0653

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0365

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.0515

Gnomad SAS AF: 0.0747

Gnomad FIN AF: 0.0566

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0509

Gnomad OTH AF: 0.0449

GnomAD2 exomes AF: 0.0517 AC: 12968 AN: 250844 AF XY: 0.0519

Gnomad AFR exome AF: 0.0657

Gnomad AMR exome AF: 0.0403

Gnomad ASJ exome AF: 0.0320

Gnomad EAS exome AF: 0.0327

Gnomad FIN exome AF: 0.0575

Gnomad NFE exome AF: 0.0497

Gnomad OTH exome AF: 0.0595

GnomAD4 exome AF: 0.0507 AC: 60580 AN: 1194690 Hom.: 1816 Cov.: 17 AF XY: 0.0515 AC XY: 31321 AN XY: 607924

African (AFR) AF: 0.0672 AC: 1892 AN: 28160

American (AMR) AF: 0.0405 AC: 1799 AN: 44372

Ashkenazi Jewish (ASJ) AF: 0.0335 AC: 819 AN: 24450

East Asian (EAS) AF: 0.0848 AC: 3259 AN: 38422

South Asian (SAS) AF: 0.0733 AC: 5945 AN: 81074

European-Finnish (FIN) AF: 0.0561 AC: 2988 AN: 53254

Middle Eastern (MID) AF: 0.0316 AC: 167 AN: 5284

European-Non Finnish (NFE) AF: 0.0475 AC: 41207 AN: 868134

Other (OTH) AF: 0.0486 AC: 2504 AN: 51540

GnomAD4 genome AF: 0.0539 AC: 8195 AN: 152130 Hom.: 231 Cov.: 32 AF XY: 0.0540 AC XY: 4017 AN XY: 74374

African (AFR) AF: 0.0655 AC: 2720 AN: 41506

American (AMR) AF: 0.0365 AC: 558 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 109 AN: 3468

East Asian (EAS) AF: 0.0520 AC: 269 AN: 5170

South Asian (SAS) AF: 0.0745 AC: 359 AN: 4818

European-Finnish (FIN) AF: 0.0566 AC: 599 AN: 10580

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0509 AC: 3462 AN: 67984

Other (OTH) AF: 0.0478 AC: 101 AN: 2114

Alfa AF: 0.0533 Hom.: 378

Bravo AF: 0.0514

Asia WGS AF: 0.0990 AC: 343 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive polycystic kidney disease Benign:1

Apr 13, 2018

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.3
DANN	Benign	0.64
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12523900; hg19: chr6-51701165; COSMIC: COSV61872455;