5-140795384-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_018905.3(PCDHA2):c.420C>G(p.Ile140Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,614,140 control chromosomes in the GnomAD database, including 12 homozygotes. 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I140L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (11 hom.)
• Consequence: PCDHA2 NM_018905.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.79

Genes affected

PCDHA2 (HGNC:8668): (protocadherin alpha 2) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA1 (HGNC:8663): (protocadherin alpha 1) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046224594).
• BP6: Variant 5-140795384-C-G is Benign according to our data. Variant chr5-140795384-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2655747.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHA2	NM_018905.3	c.420C>G	p.Ile140Met	missense_variant	1/4	ENST00000526136.2
PCDHA1	NM_018900.4	c.2394+6700C>G		intron_variant		ENST00000504120.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHA2	ENST00000526136.2	c.420C>G	p.Ile140Met	missense_variant	1/4	1	NM_018905.3	P1
PCDHA1	ENST00000504120.4	c.2394+6700C>G		intron_variant		1	NM_018900.4	P1
	ENST00000655235.1	n.658-6530G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 328 AN: 152128 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00641

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00220 AC: 554 AN: 251494 Hom.: 3 AF XY: 0.00238 AC XY: 324 AN XY: 135922

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00270

Gnomad OTH exome AF: 0.00586

GnomAD4 exome AF: 0.00243 AC: 3550 AN: 1461894 Hom.: 11 Cov.: 34 AF XY: 0.00240 AC XY: 1748 AN XY: 727248

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00407

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00152

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.00262

Gnomad4 OTH exome AF: 0.00275

GnomAD4 genome AF: 0.00215 AC: 327 AN: 152246 Hom.: 1 Cov.: 33 AF XY: 0.00218 AC XY: 162 AN XY: 74434

Gnomad4 AFR AF: 0.000482

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00266

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.00244

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00199 AC: 242

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

PCDHA1: BS2; PCDHA2: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	5.2
Dann	Benign	0.77
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.39	T;T;T
MetaRNN	Benign	0.0046	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	M;M;M
MutationTaster	Benign	1.0	N;N;N;N;N
PROVEAN	Benign	-0.42	N;N;N
REVEL	Benign	0.095
Sift	Uncertain	0.026	D;D;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		0.56	P;P;B
Vest4		0.28
MVP		0.46
ClinPred		0.0063	T
GERP RS		-2.8
Varity_R		0.11
gMVP		0.16

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: rs144974749; hg19: chr5-140174969;