rs142522748

Variant names:

• chr6-51772738-G-T
• rs142522748
• NM_138694.4:c.8606C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-51772738-G-T
• chr6-51772738-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_138694.4(PKHD1):​c.8606C>A​(p.Thr2869Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0117 in 1,597,930 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2869T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (11 hom., cov: 31)
  • Exomes 𝑓: 0.012 (152 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.54
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020076126).
• BP6: Variant 6-51772738-G-T is Benign according to our data. Variant chr6-51772738-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0102 (1548/151964) while in subpopulation NFE AF = 0.0164 (1114/67924). AF 95% confidence interval is 0.0156. There are 11 homozygotes in GnomAd4. There are 704 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

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.8606C>A	p.Thr2869Lys	missense	Exon 55 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.8606C>A	p.Thr2869Lys	missense	Exon 55 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.8606C>A	p.Thr2869Lys	missense	Exon 55 of 67	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.8606C>A	p.Thr2869Lys	missense	Exon 55 of 61	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1547 AN: 151846 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00849

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00945

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0164

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00927 AC: 2325 AN: 250704 AF XY: 0.00908

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00642

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00924

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.0118 AC: 17087 AN: 1445966 Hom.: 152 Cov.: 26 AF XY: 0.0118 AC XY: 8535 AN XY: 720306

African (AFR) AF: 0.00130 AC: 43 AN: 33174

American (AMR) AF: 0.00681 AC: 304 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 391 AN: 25992

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39536

South Asian (SAS) AF: 0.000791 AC: 68 AN: 85950

European-Finnish (FIN) AF: 0.00908 AC: 484 AN: 53308

Middle Eastern (MID) AF: 0.00471 AC: 27 AN: 5728

European-Non Finnish (NFE) AF: 0.0138 AC: 15115 AN: 1097824

Other (OTH) AF: 0.0109 AC: 654 AN: 59840

GnomAD4 genome AF: 0.0102 AC: 1548 AN: 151964 Hom.: 11 Cov.: 31 AF XY: 0.00948 AC XY: 704 AN XY: 74232

African (AFR) AF: 0.00260 AC: 108 AN: 41514

American (AMR) AF: 0.00855 AC: 130 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3468

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5140

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4816

European-Finnish (FIN) AF: 0.00945 AC: 100 AN: 10582

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0164 AC: 1114 AN: 67924

Other (OTH) AF: 0.0104 AC: 22 AN: 2108

Alfa AF: 0.0141 Hom.: 54

Bravo AF: 0.00889

TwinsUK AF: 0.0159 AC: 59

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0134 AC: 115

ExAC AF: 0.00930 AC: 1129

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.0138

EpiControl AF: 0.0123

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Autosomal recessive polycystic kidney disease (5)
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Caroli disease (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.020	T
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.5
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.98	D
Vest4		0.84
MVP		0.99
MPC		0.40
ClinPred		0.035	T
GERP RS		4.9
Varity_R		0.82
gMVP		0.95
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs142522748; hg19: chr6-51637536; COSMIC: COSV61868162;