6-52017489-C-G

Variant names:

• chr6-52017489-C-G
• rs913487671
• NM_138694.4:c.5521G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_138694.4(PKHD1):​c.5521G>C​(p.Glu1841Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1841K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.08
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_138694.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-52017489-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 551774.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.5521G>C	p.Glu1841Gln	missense_variant	Exon 34 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.5521G>C	p.Glu1841Gln	missense_variant	Exon 34 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.5521G>C	p.Glu1841Gln	missense_variant	Exon 34 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.5	M;M
PhyloP100		3.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.28	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.99	D;D
Vest4		0.37
MutPred		0.51		Loss of sheet (P = 0.0037);Loss of sheet (P = 0.0037);
MVP		0.95
MPC		0.28
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.14
gMVP		0.65
Mutation Taster		=48/52	disease causing

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: rs913487671; hg19: chr6-51882287; COSMIC: COSV61867264;