rs143737660

Positions:

• chr6-51748214-C-A
• chr6-51748214-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000371117.8(PKHD1):​c.9402G>T​(p.Lys3134Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. K3134E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PKHD1 ENST00000371117.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.613

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21066368).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.9402G>T	p.Lys3134Asn	missense_variant	58/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.9402G>T	p.Lys3134Asn	missense_variant	58/67	1	NM_138694.4	ENSP00000360158	P2
PKHD1	ENST00000340994.4	c.9402G>T	p.Lys3134Asn	missense_variant	58/61	5		ENSP00000341097	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461792 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.012	D;D
Sift4G	Benign	0.061	T;T
Polyphen		0.73	P;P
Vest4		0.32
MutPred		0.35		Loss of ubiquitination at K3134 (P = 0.011);Loss of ubiquitination at K3134 (P = 0.011);
MVP		0.76
MPC		0.33
ClinPred		0.48	T
GERP RS		3.0
Varity_R		0.10
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs143737660; hg19: chr6-51613012;