6-52054122-A-T

Variant names:

• chr6-52054122-A-T
• rs786204696
• NM_138694.4:c.1880T>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_138694.4(PKHD1):​c.1880T>A​(p.Met627Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,460,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.06
• Publications: 4 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: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 6-52054122-A-T is Pathogenic according to our data. Variant chr6-52054122-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 189098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1880T>A	p.Met627Lys	missense	Exon 20 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.1880T>A	p.Met627Lys	missense	Exon 20 of 61	NP_733842.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.1880T>A	p.Met627Lys	missense	Exon 20 of 67	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.1880T>A	p.Met627Lys	missense	Exon 20 of 61	ENSP00000341097.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460604 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 726690

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110874

Other (OTH) AF: 0.0000497 AC: 3 AN: 60342

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Autosomal recessive polycystic kidney disease (3)
1	-	-	Autosomal dominant polycystic liver disease (1)
1	-	-	Polycystic kidney disease 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	2.0	M
PhyloP100		6.1
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.47	P
Vest4		0.72
MutPred		0.85		Loss of sheet (P = 0.007)
MVP		0.90
MPC		0.15
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.75
gMVP		0.79
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs786204696; hg19: chr6-51918920;