rs9370096

Variant names:

• chr6-52050158-G-A
• rs9370096
• NM_138694.4:c.2278C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-52050158-G-A
• chr6-52050158-G-C
• chr6-52050158-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 4P and 20B. PM1 PM5 BP4_Strong BP6_Very_Strong BA1

The NM_138694.4(PKHD1):​c.2278C>T​(p.Arg760Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 1,613,046 control chromosomes in the GnomAD database, including 203,806 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R760H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.41 (14960 hom., cov: 33)
  • Exomes 𝑓: 0.50 (188846 hom.)
• Consequence: PKHD1 NM_138694.4 missense, splice_region
• Scores: Splicing: ADA: 0.0002700
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.479
• Publications: 42 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 -16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 9 uncertain in NM_138694.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-52050157-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 188876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=7.792624E-6).
• BP6: Variant 6-52050158-G-A is Benign according to our data. Variant chr6-52050158-G-A is described in ClinVar as Benign. ClinVar VariationId is 96386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.558 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.2278C>T	p.Arg760Cys	missense splice_region	Exon 22 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.2278C>T	p.Arg760Cys	missense splice_region	Exon 22 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.2278C>T	p.Arg760Cys	missense splice_region	Exon 22 of 67	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.2278C>T	p.Arg760Cys	missense splice_region	Exon 22 of 61	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62609 AN: 152006 Hom.: 14962 Cov.: 33

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.568

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.448

GnomAD2 exomes AF: 0.476 AC: 119448 AN: 250924 AF XY: 0.470

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.651

Gnomad ASJ exome AF: 0.497

Gnomad EAS exome AF: 0.381

Gnomad FIN exome AF: 0.480

Gnomad NFE exome AF: 0.518

Gnomad OTH exome AF: 0.510

GnomAD4 exome AF: 0.501 AC: 732307 AN: 1460922 Hom.: 188846 Cov.: 46 AF XY: 0.498 AC XY: 361609 AN XY: 726782

African (AFR) AF: 0.146 AC: 4896 AN: 33470

American (AMR) AF: 0.636 AC: 28444 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 13029 AN: 26124

East Asian (EAS) AF: 0.369 AC: 14655 AN: 39672

South Asian (SAS) AF: 0.341 AC: 29426 AN: 86228

European-Finnish (FIN) AF: 0.500 AC: 26690 AN: 53412

Middle Eastern (MID) AF: 0.429 AC: 2436 AN: 5680

European-Non Finnish (NFE) AF: 0.525 AC: 583630 AN: 1111272

Other (OTH) AF: 0.482 AC: 29101 AN: 60352

GnomAD4 genome AF: 0.412 AC: 62609 AN: 152124 Hom.: 14960 Cov.: 33 AF XY: 0.409 AC XY: 30409 AN XY: 74364

African (AFR) AF: 0.159 AC: 6611 AN: 41518

American (AMR) AF: 0.568 AC: 8682 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 1746 AN: 3468

East Asian (EAS) AF: 0.382 AC: 1977 AN: 5178

South Asian (SAS) AF: 0.332 AC: 1596 AN: 4812

European-Finnish (FIN) AF: 0.472 AC: 4990 AN: 10572

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.523 AC: 35522 AN: 67972

Other (OTH) AF: 0.444 AC: 939 AN: 2114

Alfa AF: 0.468 Hom.: 40432

Bravo AF: 0.410

TwinsUK AF: 0.528 AC: 1959

ALSPAC AF: 0.511 AC: 1970

ESP6500AA AF: 0.151 AC: 667

ESP6500EA AF: 0.510 AC: 4388

ExAC AF: 0.465 AC: 56427

Asia WGS AF: 0.322 AC: 1123 AN: 3478

EpiCase AF: 0.517

EpiControl AF: 0.512

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)
-	-	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
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.6
DANN	Benign	0.96
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0000078	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.49	N
PhyloP100		-0.48
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.22
Sift	Benign	0.23	T
Sift4G	Benign	0.12	T
Polyphen		0.0070	B
Vest4		0.037
MPC		0.079
ClinPred		0.0099	T
GERP RS		-6.3
Varity_R		0.078
gMVP		0.47
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.034
SpliceAI score (max)		0.11		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: rs9370096; hg19: chr6-51914956; COSMIC: COSV61863770;