rs12529717

Variant names:

• chr6-51830843-T-C
• rs12529717
• NM_138694.4:c.8302+18A>G

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.8302+18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0507 in 1,609,690 control chromosomes in the GnomAD database, including 2,357 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (224 hom., cov: 32)
  • Exomes 𝑓: 0.050 (2133 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.627
• 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: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), 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=-0.92).
• BP6: Variant 6-51830843-T-C is Benign according to our data. Variant chr6-51830843-T-C is described in ClinVar as Benign. ClinVar VariationId is 96430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0663 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	NM_138694.4	MANE Select	c.8302+18A>G		intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.8302+18A>G		intron	N/A	NP_733842.2	P08F94-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.8302+18A>G		intron	N/A	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.8302+18A>G		intron	N/A	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.0529 AC: 8051 AN: 152098 Hom.: 223 Cov.: 32

Gnomad AFR AF: 0.0602

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0362

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.0522

Gnomad SAS AF: 0.0727

Gnomad FIN AF: 0.0566

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0523

Gnomad OTH AF: 0.0430

GnomAD2 exomes AF: 0.0522 AC: 13110 AN: 251020 AF XY: 0.0527

Gnomad AFR exome AF: 0.0606

Gnomad AMR exome AF: 0.0400

Gnomad ASJ exome AF: 0.0360

Gnomad EAS exome AF: 0.0332

Gnomad FIN exome AF: 0.0582

Gnomad NFE exome AF: 0.0509

Gnomad OTH exome AF: 0.0602

GnomAD4 exome AF: 0.0505 AC: 73588 AN: 1457474 Hom.: 2133 Cov.: 28 AF XY: 0.0513 AC XY: 37231 AN XY: 725268

African (AFR) AF: 0.0601 AC: 2002 AN: 33320

American (AMR) AF: 0.0402 AC: 1793 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.0380 AC: 990 AN: 26042

East Asian (EAS) AF: 0.0836 AC: 3312 AN: 39614

South Asian (SAS) AF: 0.0733 AC: 6316 AN: 86182

European-Finnish (FIN) AF: 0.0568 AC: 3033 AN: 53368

Middle Eastern (MID) AF: 0.0318 AC: 183 AN: 5750

European-Non Finnish (NFE) AF: 0.0479 AC: 53043 AN: 1108396

Other (OTH) AF: 0.0485 AC: 2916 AN: 60174

GnomAD4 genome AF: 0.0530 AC: 8070 AN: 152216 Hom.: 224 Cov.: 32 AF XY: 0.0530 AC XY: 3943 AN XY: 74414

African (AFR) AF: 0.0602 AC: 2501 AN: 41548

American (AMR) AF: 0.0363 AC: 555 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3470

East Asian (EAS) AF: 0.0527 AC: 273 AN: 5182

South Asian (SAS) AF: 0.0726 AC: 350 AN: 4824

European-Finnish (FIN) AF: 0.0566 AC: 600 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0523 AC: 3555 AN: 67990

Other (OTH) AF: 0.0459 AC: 97 AN: 2114

Alfa AF: 0.0568 Hom.: 93

Bravo AF: 0.0502

Asia WGS AF: 0.0960 AC: 332 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Autosomal recessive polycystic kidney disease (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.30
DANN	Benign	0.40
PhyloP100		-0.63
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: rs12529717; hg19: chr6-51695641; COSMIC: COSV61872443;