chr5-141854213-T-G

Position:

• chr5-141854213-T-G

Variant summary

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

The NM_032420.5(PCDH1):​c.3543A>C​(p.Lys1181Asn) 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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCDH1 NM_032420.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.12

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]

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=0.15259564).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH1	NM_032420.5	c.3543A>C	p.Lys1181Asn	missense_variant	5/5	ENST00000287008.8	NP_115796.2
PCDH1	XM_005268452.4	c.3591A>C	p.Lys1197Asn	missense_variant	5/5		XP_005268509.2
PCDH1	XM_017009517.3	c.2406A>C	p.Lys802Asn	missense_variant	4/4		XP_016865006.1
PCDH1	XM_005268454.6	c.*237A>C		3_prime_UTR_variant	6/6		XP_005268511.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH1	ENST00000287008.8	c.3543A>C	p.Lys1181Asn	missense_variant	5/5	5	NM_032420.5	ENSP00000287008.3
PCDH1	ENST00000503492	c.*237A>C		3_prime_UTR_variant	5/5	5		ENSP00000424667.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.3543A>C (p.K1181N) alteration is located in exon 5 (coding exon 5) of the PCDH1 gene. This alteration results from a A to C substitution at nucleotide position 3543, causing the lysine (K) at amino acid position 1181 to be replaced by an asparagine (N). 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	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	22
DANN	Benign	0.87
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.082
Sift	Benign	1.0	T
Sift4G	Benign	0.60	T
Polyphen		0.56	P
Vest4		0.39
MutPred		0.36		Loss of ubiquitination at K1181 (P = 6e-04);
MVP		0.33
MPC		0.62
ClinPred		0.37	T
GERP RS		3.6
gMVP		0.39

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: chr5-141233778;