chr5-141854391-C-G

Variant names:

• chr5-141854391-C-G
• rs768852148
• NM_032420.5:c.3365G>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_032420.5(PCDH1):​c.3365G>C​(p.Arg1122Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PCDH1 NM_032420.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.49

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH1	NM_032420.5	c.3365G>C	p.Arg1122Pro	missense_variant	Exon 5 of 5	ENST00000287008.8	NP_115796.2
PCDH1	XM_005268452.4	c.3413G>C	p.Arg1138Pro	missense_variant	Exon 5 of 5		XP_005268509.2
PCDH1	XM_017009517.3	c.2228G>C	p.Arg743Pro	missense_variant	Exon 4 of 4		XP_016865006.1
PCDH1	XM_005268454.6	c.*59G>C		3_prime_UTR_variant	Exon 6 of 6		XP_005268511.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH1	ENST00000287008.8	c.3365G>C	p.Arg1122Pro	missense_variant	Exon 5 of 5	5	NM_032420.5	ENSP00000287008.3
PCDH1	ENST00000503492	c.*59G>C		3_prime_UTR_variant	Exon 5 of 5	5		ENSP00000424667.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460876 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726734

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: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3365G>C (p.R1122P) alteration is located in exon 5 (coding exon 5) of the PCDH1 gene. This alteration results from a G to C substitution at nucleotide position 3365, causing the arginine (R) at amino acid position 1122 to be replaced by a proline (P). 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	-0.41
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.87	T
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.14
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.17		Gain of glycosylation at T1119 (P = 0.0234);
MVP		0.13
MPC		1.3
ClinPred		0.90	D
GERP RS		2.7
gMVP		0.71

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

Other links and lift over

dbSNP: rs768852148; hg19: chr5-141233956;