rs9474143

Variant names:

• chr6-52082439-G-A
• rs9474143
• NM_138694.4:c.234C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-52082439-G-A
• chr6-52082439-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_138694.4(PKHD1):​c.234C>T​(p.Asp78Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,612,848 control chromosomes in the GnomAD database, including 56,908 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7247 hom., cov: 32)
  • Exomes 𝑓: 0.25 (49661 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.45
• Publications: 20 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-52082439-G-A is Benign according to our data. Variant chr6-52082439-G-A is described in ClinVar as Benign. ClinVar VariationId is 96388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.45 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.427 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.234C>T	p.Asp78Asp	synonymous	Exon 4 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.234C>T	p.Asp78Asp	synonymous	Exon 4 of 61	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.234C>T	p.Asp78Asp	synonymous	Exon 4 of 67	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.234C>T	p.Asp78Asp	synonymous	Exon 4 of 61	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45583 AN: 151860 Hom.: 7238 Cov.: 32

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.376

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.279

GnomAD2 exomes AF: 0.283 AC: 71060 AN: 251366 AF XY: 0.287

Gnomad AFR exome AF: 0.387

Gnomad AMR exome AF: 0.205

Gnomad ASJ exome AF: 0.258

Gnomad EAS exome AF: 0.443

Gnomad FIN exome AF: 0.317

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.265

GnomAD4 exome AF: 0.255 AC: 371930 AN: 1460868 Hom.: 49661 Cov.: 35 AF XY: 0.257 AC XY: 186713 AN XY: 726782

African (AFR) AF: 0.389 AC: 13023 AN: 33450

American (AMR) AF: 0.212 AC: 9475 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 6670 AN: 26132

East Asian (EAS) AF: 0.434 AC: 17245 AN: 39698

South Asian (SAS) AF: 0.359 AC: 30994 AN: 86230

European-Finnish (FIN) AF: 0.297 AC: 15853 AN: 53414

Middle Eastern (MID) AF: 0.294 AC: 1697 AN: 5768

European-Non Finnish (NFE) AF: 0.235 AC: 260590 AN: 1111074

Other (OTH) AF: 0.271 AC: 16383 AN: 60378

GnomAD4 genome AF: 0.300 AC: 45614 AN: 151980 Hom.: 7247 Cov.: 32 AF XY: 0.305 AC XY: 22686 AN XY: 74294

African (AFR) AF: 0.391 AC: 16205 AN: 41436

American (AMR) AF: 0.242 AC: 3693 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 883 AN: 3468

East Asian (EAS) AF: 0.442 AC: 2273 AN: 5138

South Asian (SAS) AF: 0.377 AC: 1814 AN: 4816

European-Finnish (FIN) AF: 0.323 AC: 3408 AN: 10558

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16449 AN: 67972

Other (OTH) AF: 0.279 AC: 588 AN: 2108

Alfa AF: 0.260 Hom.: 11834

Bravo AF: 0.296

Asia WGS AF: 0.399 AC: 1383 AN: 3478

EpiCase AF: 0.245

EpiControl AF: 0.245

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.059
DANN	Benign	0.43
PhyloP100		-1.5
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs9474143; hg19: chr6-51947237; COSMIC: COSV61861118;