rs146519878

Variant names:

• chr6-51747828-A-G
• rs146519878
• NM_138694.4:c.9788T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_138694.4(PKHD1):​c.9788T>C​(p.Val3263Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,613,826 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V3263V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0025 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (10 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 3.40
• Publications: 9 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064140856).
• BP6: Variant 6-51747828-A-G is Benign according to our data. Variant chr6-51747828-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167477.
• BS2: High Homozygotes in GnomAd4 at 4 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.9788T>C	p.Val3263Ala	missense	Exon 58 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.9788T>C	p.Val3263Ala	missense	Exon 58 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.9788T>C	p.Val3263Ala	missense	Exon 58 of 67	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.9788T>C	p.Val3263Ala	missense	Exon 58 of 61	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 378 AN: 152100 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00167 AC: 420 AN: 251166 AF XY: 0.00168

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00321

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00306 AC: 4468 AN: 1461608 Hom.: 10 Cov.: 33 AF XY: 0.00298 AC XY: 2168 AN XY: 727120

African (AFR) AF: 0.000658 AC: 22 AN: 33460

American (AMR) AF: 0.000985 AC: 44 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86256

European-Finnish (FIN) AF: 0.000487 AC: 26 AN: 53418

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5762

European-Non Finnish (NFE) AF: 0.00378 AC: 4202 AN: 1111814

Other (OTH) AF: 0.00250 AC: 151 AN: 60380

GnomAD4 genome AF: 0.00248 AC: 378 AN: 152218 Hom.: 4 Cov.: 32 AF XY: 0.00226 AC XY: 168 AN XY: 74414

African (AFR) AF: 0.000674 AC: 28 AN: 41550

American (AMR) AF: 0.00131 AC: 20 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00338 AC: 230 AN: 67998

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00286 Hom.: 5

Bravo AF: 0.00290

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00173 AC: 210

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00365

EpiControl AF: 0.00332

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Autosomal recessive polycystic kidney disease (2)
-	-	2	not provided (2)
-	1	1	not specified (2)
-	1	-	Autosomal dominant polycystic liver disease (1)
-	-	1	PKHD1-related disorder (1)
-	1	-	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.4
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.34
Sift	Benign	0.18	T
Sift4G	Uncertain	0.014	D
Polyphen		0.91	P
Vest4		0.39
MVP		0.92
MPC		0.18
ClinPred		0.032	T
GERP RS		5.7
Varity_R		0.11
gMVP		0.62
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs146519878; hg19: chr6-51612626; COSMIC: COSV99049429;