dbSNP rs867558508: PCDH7:p.Glu181Lys (chr4-30721963-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001173523.2(PCDH7):c.541G>A(p.Glu181Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PCDH7
NM_001173523.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.68

Variant links:

Genes affected

PCDH7 (HGNC:8659): (protocadherin 7) This gene belongs to the protocadherin gene family, a subfamily of the cadherin superfamily. The gene encodes a protein with an extracellular domain containing 7 cadherin repeats. The gene product is an integral membrane protein that is thought to function in cell-cell recognition and adhesion. Alternative splicing yields isoforms with unique cytoplasmic tails. [provided by RefSeq, Jul 2008]

PCDH7 links:

ENSG00000286596 (HGNC:):

ENSG00000286596 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH7	NM_001173523.2 link	c.541G>A	p.Glu181Lys	missense_variant	Exon 1 of 3	ENST00000695919.1	NP_001166994.1	A0A8Q3SI70
PCDH7	NM_032457.4 link	c.541G>A	p.Glu181Lys	missense_variant	Exon 1 of 3		NP_115833.2	A0A8V8TM73
PCDH7	NM_002589.4 link	c.541G>A	p.Glu181Lys	missense_variant	Exon 1 of 2		NP_002580.2	O60245-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH7	ENST00000695919.1 link	c.541G>A	p.Glu181Lys	missense_variant	Exon 1 of 3		NM_001173523.2	ENSP00000512266.1		A0A8Q3SI70

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1359944

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

671884

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.541G>A (p.E181K) alteration is located in exon 1 (coding exon 1) of the PCDH7 gene. This alteration results from a G to A substitution at nucleotide position 541, causing the glutamic acid (E) at amino acid position 181 to be replaced by a lysine (K). 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

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.060

T;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.92

D;D

M_CAP

Pathogenic

0.42

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.14

N;N

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-2.1

N;N

REVEL

Uncertain

0.39

Sift

Uncertain

0.0090

D;D

Sift4G

Benign

0.33

T;T

Polyphen

0.99

D;.

Vest4

0.56

MutPred

0.47

Gain of ubiquitination at E181 (P = 0.0045);Gain of ubiquitination at E181 (P = 0.0045);

MVP

0.58

ClinPred

0.92

GERP RS

5.2

Varity_R

0.35

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over