6-51903686-T-C

Variant names:

• chr6-51903686-T-C
• NM_138694.4:c.6907A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_138694.4(PKHD1):​c.6907A>G​(p.Ile2303Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,459,202 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I2303F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.55

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-51903686-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.6907A>G	p.Ile2303Val	missense_variant	Exon 43 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.6907A>G	p.Ile2303Val	missense_variant	Exon 43 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.6907A>G	p.Ile2303Val	missense_variant	Exon 43 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459202 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726090

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.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T;T
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.050	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.64	T;T
Sift4G	Uncertain	0.040	D;D
Polyphen		0.99	D;P
Vest4		0.47
MutPred		0.38		Gain of catalytic residue at I2303 (P = 0.0648);Gain of catalytic residue at I2303 (P = 0.0648);
MVP		0.93
MPC		0.35
ClinPred		0.74	D
GERP RS		5.9
Varity_R		0.062
gMVP		0.57

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-51768484;