6-52024560-T-C

Variant names:

• chr6-52024560-T-C
• rs12210725
• NM_138694.4:c.5236+14A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_138694.4(PKHD1):​c.5236+14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 1,612,358 control chromosomes in the GnomAD database, including 1,005 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (59 hom., cov: 32)
  • Exomes 𝑓: 0.030 (946 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.160
• Publications: 3 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 -16 ACMG points.

• BP6: Variant 6-52024560-T-C is Benign according to our data. Variant chr6-52024560-T-C is described in ClinVar as Benign. ClinVar VariationId is 96405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0778 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.5236+14A>G		intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.5236+14A>G		intron	N/A	NP_733842.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.5236+14A>G		intron	N/A	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.5236+14A>G		intron	N/A	ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3225 AN: 152172 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.00540

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.0841

Gnomad FIN AF: 0.00678

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0295

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.0290 AC: 7243 AN: 249568 AF XY: 0.0323

Gnomad AFR exome AF: 0.00415

Gnomad AMR exome AF: 0.0130

Gnomad ASJ exome AF: 0.0192

Gnomad EAS exome AF: 0.00474

Gnomad FIN exome AF: 0.00911

Gnomad NFE exome AF: 0.0311

Gnomad OTH exome AF: 0.0266

GnomAD4 exome AF: 0.0304 AC: 44348 AN: 1460068 Hom.: 946 Cov.: 32 AF XY: 0.0320 AC XY: 23263 AN XY: 726480

African (AFR) AF: 0.00433 AC: 145 AN: 33466

American (AMR) AF: 0.0140 AC: 626 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0201 AC: 524 AN: 26130

East Asian (EAS) AF: 0.00186 AC: 74 AN: 39698

South Asian (SAS) AF: 0.0845 AC: 7283 AN: 86202

European-Finnish (FIN) AF: 0.0102 AC: 544 AN: 53164

Middle Eastern (MID) AF: 0.0323 AC: 186 AN: 5766

European-Non Finnish (NFE) AF: 0.0300 AC: 33359 AN: 1110568

Other (OTH) AF: 0.0266 AC: 1607 AN: 60352

GnomAD4 genome AF: 0.0212 AC: 3229 AN: 152290 Hom.: 59 Cov.: 32 AF XY: 0.0216 AC XY: 1609 AN XY: 74460

African (AFR) AF: 0.00539 AC: 224 AN: 41570

American (AMR) AF: 0.0137 AC: 210 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3470

East Asian (EAS) AF: 0.00444 AC: 23 AN: 5180

South Asian (SAS) AF: 0.0846 AC: 408 AN: 4824

European-Finnish (FIN) AF: 0.00678 AC: 72 AN: 10618

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0295 AC: 2005 AN: 68020

Other (OTH) AF: 0.0180 AC: 38 AN: 2108

Alfa AF: 0.0239 Hom.: 14

Bravo AF: 0.0209

Asia WGS AF: 0.0380 AC: 135 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Autosomal recessive polycystic kidney disease (3)
-	-	2	Polycystic kidney disease 4 (2)
-	-	1	not provided (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	15
DANN	Benign	0.44
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.42		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12210725; hg19: chr6-51889358; COSMIC: COSV107435524;