chr7-47846960-C-A

Variant names:

• chr7-47846960-C-A
• rs886037834
• NM_138295.5:c.5072G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_138295.5(PKD1L1):​c.5072G>T​(p.Cys1691Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. C1691S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PKD1L1 NM_138295.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.80
• Publications: 0 publications found

Genes affected

PKD1L1 (HGNC:18053): (polycystin 1 like 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family containing 11 transmembrane domains, a receptor for egg jelly (REJ) domain, and a polycystin-1, lipoxygenase, alpha-toxin (PLAT) domain. The encoded protein may play a role in the male reproductive system. Alternative splice variants have been described but their biological nature has not been determined. [provided by RefSeq, Jul 2008]

PKD1L1 Gene-Disease associations (from GenCC):

• heterotaxy, visceral, 8, autosomal

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• situs inversus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-47846960-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235198.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1L1	NM_138295.5	c.5072G>T	p.Cys1691Phe	missense_variant	Exon 32 of 57	ENST00000289672.7	NP_612152.1
PKD1L1	XM_017011798.3	c.5249G>T	p.Cys1750Phe	missense_variant	Exon 33 of 59		XP_016867287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1L1	ENST00000289672.7	c.5072G>T	p.Cys1691Phe	missense_variant	Exon 32 of 57	1	NM_138295.5	ENSP00000289672.2
PKD1L1	ENST00000690269.1	c.5072G>T	p.Cys1691Phe	missense_variant	Exon 32 of 58			ENSP00000510743.1
PKD1L1	ENST00000685709.1	c.4904G>T	p.Cys1635Phe	missense_variant	Exon 31 of 56			ENSP00000509540.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.053	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.77		Loss of sheet (P = 0.0181);
MVP		0.93
MPC		0.61
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.94
gMVP		0.66
Mutation Taster		=42/58	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: rs886037834; hg19: chr7-47886558;