chr5-141857305-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_032420.5(PCDH1):ā€‹c.3266A>Gā€‹(p.Tyr1089Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

PCDH1
NM_032420.5 missense

Scores

9
4
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.67
Variant links:
Genes affected
PCDH1 (HGNC:8655): (protocadherin 1) This gene belongs to the protocadherin subfamily within the cadherin superfamily. The encoded protein is a membrane protein found at cell-cell boundaries. It is involved in neural cell adhesion, suggesting a possible role in neuronal development. The protein includes an extracelllular region, containing 7 cadherin-like domains, a transmembrane region and a C-terminal cytoplasmic region. Cells expressing the protein showed cell aggregation activity. Alternative splicing occurs in this gene. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.79

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PCDH1NM_032420.5 linkuse as main transcriptc.3266A>G p.Tyr1089Cys missense_variant 4/5 ENST00000287008.8 NP_115796.2 Q08174-2B4E2D8
PCDH1XM_005268452.4 linkuse as main transcriptc.3314A>G p.Tyr1105Cys missense_variant 4/5 XP_005268509.2
PCDH1XM_005268454.6 linkuse as main transcriptc.3314A>G p.Tyr1105Cys missense_variant 4/6 XP_005268511.2
PCDH1XM_017009517.3 linkuse as main transcriptc.2129A>G p.Tyr710Cys missense_variant 3/4 XP_016865006.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PCDH1ENST00000287008.8 linkuse as main transcriptc.3266A>G p.Tyr1089Cys missense_variant 4/55 NM_032420.5 ENSP00000287008.3 Q08174-2
PCDH1ENST00000503492.5 linkuse as main transcriptc.1070A>G p.Tyr357Cys missense_variant 3/55 ENSP00000424667.1 D6RAX3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000801
AC:
2
AN:
249784
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135008
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460664
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
726590
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 02, 2023The c.3266A>G (p.Y1089C) alteration is located in exon 4 (coding exon 4) of the PCDH1 gene. This alteration results from a A to G substitution at nucleotide position 3266, causing the tyrosine (Y) at amino acid position 1089 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.19
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Benign
0.060
.;T
Eigen
Pathogenic
0.73
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.79
D;D
MetaSVM
Uncertain
-0.26
T
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-4.9
D;N
REVEL
Uncertain
0.37
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.89
MutPred
0.27
Loss of phosphorylation at Y1089 (P = 0.0034);.;
MVP
0.44
MPC
1.5
ClinPred
0.99
D
GERP RS
5.2
gMVP
0.61

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1415892100; hg19: chr5-141236870; COSMIC: COSV99746204; API