6-52025705-G-T

Variant names:

• chr6-52025705-G-T
• rs368974211
• NM_138694.4:c.4105C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_138694.4(PKHD1):​c.4105C>A​(p.Arg1369Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.897

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.4105C>A	p.Arg1369Ser	missense_variant	Exon 32 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.4105C>A	p.Arg1369Ser	missense_variant	Exon 32 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.4105C>A	p.Arg1369Ser	missense_variant	Exon 32 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 12, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	0.00090	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	16
DANN	Benign	0.62
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.41	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.46	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.68	P;P
Vest4		0.38
MutPred		0.43		Gain of ubiquitination at K1371 (P = 0.0635);Gain of ubiquitination at K1371 (P = 0.0635);
MVP		0.89
MPC		0.14
ClinPred		0.19	T
GERP RS		0.47
Varity_R		0.085
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.61		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs368974211; hg19: chr6-51890503;