5-141854406-G-A

Position:

• chr5-141854406-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_032420.5(PCDH1):​c.3350C>T​(p.Thr1117Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,612,162 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (16 hom.)
• Consequence: PCDH1 NM_032420.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 9.50

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03884679).
• BP6: Variant 5-141854406-G-A is Benign according to our data. Variant chr5-141854406-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 787045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 299 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH1	NM_032420.5	c.3350C>T	p.Thr1117Ile	missense_variant	5/5	ENST00000287008.8	NP_115796.2
PCDH1	XM_005268452.4	c.3398C>T	p.Thr1133Ile	missense_variant	5/5		XP_005268509.2
PCDH1	XM_017009517.3	c.2213C>T	p.Thr738Ile	missense_variant	4/4		XP_016865006.1
PCDH1	XM_005268454.6	c.*44C>T		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.3350C>T	p.Thr1117Ile	missense_variant	5/5	5	NM_032420.5	ENSP00000287008.3
PCDH1	ENST00000503492	c.*44C>T		3_prime_UTR_variant	5/5	5		ENSP00000424667.1

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 299 AN: 152180 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00366

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00189 AC: 464 AN: 245946 Hom.: 3 AF XY: 0.00179 AC XY: 239 AN XY: 133732

Gnomad AFR exome AF: 0.000965

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00274

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00163

Gnomad NFE exome AF: 0.00330

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00326 AC: 4753 AN: 1459864 Hom.: 16 Cov.: 31 AF XY: 0.00309 AC XY: 2247 AN XY: 726072

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.000381

Gnomad4 ASJ exome AF: 0.00307

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00158

Gnomad4 NFE exome AF: 0.00399

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00196 AC: 299 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.00179 AC XY: 133 AN XY: 74456

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00366

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00288 Hom.: 1

Bravo AF: 0.00172

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000912 AC: 4

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00186 AC: 226

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00344

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.37	T
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.71
MVP		0.29
MPC		1.4
ClinPred		0.045	T
GERP RS		4.6
gMVP		0.44

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: rs75207818; hg19: chr5-141233971;