5-140788566-G-T

Variant names:

• chr5-140788566-G-T
• rs2240695
• NM_018900.4:c.2276G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018900.4(PCDHA1):​c.2276G>T​(p.Cys759Phe) variant causes a missense change. The variant allele was found at a frequency of 0.527 in 1,613,562 control chromosomes in the GnomAD database, including 224,522 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.51 (20263 hom., cov: 33)
  • Exomes 𝑓: 0.53 (204259 hom.)
• Consequence: PCDHA1 NM_018900.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.62
• Publications: 34 publications found

Genes affected

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]

ENSG00000279726 (HGNC:):

PCDHA@ (HGNC:8662):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.6917458E-4).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018900.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHA1	NM_018900.4	MANE Select	c.2276G>T	p.Cys759Phe	missense	Exon 1 of 4	NP_061723.1
	PCDHA1	NM_031410.3		c.2276G>T	p.Cys759Phe	missense	Exon 1 of 1	NP_113598.1
	PCDHA1	NM_031411.3		c.1602+674G>T		intron	N/A	NP_113599.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHA1	ENST00000504120.4	TSL:1 MANE Select	c.2276G>T	p.Cys759Phe	missense	Exon 1 of 4	ENSP00000420840.3
	ENSG00000279726	ENST00000624712.1	TSL:1	n.944C>A		non_coding_transcript_exon	Exon 2 of 2
	PCDHA1	ENST00000394633.7	TSL:1	c.1602+674G>T		intron	N/A	ENSP00000378129.3

Frequencies

GnomAD3 genomes AF: 0.514 AC: 78076 AN: 151896 Hom.: 20246 Cov.: 33

Gnomad AFR AF: 0.484

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.523

Gnomad EAS AF: 0.522

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.530

Gnomad OTH AF: 0.523

GnomAD2 exomes AF: 0.525 AC: 131704 AN: 250672 AF XY: 0.527

Gnomad AFR exome AF: 0.483

Gnomad AMR exome AF: 0.554

Gnomad ASJ exome AF: 0.525

Gnomad EAS exome AF: 0.539

Gnomad FIN exome AF: 0.452

Gnomad NFE exome AF: 0.530

Gnomad OTH exome AF: 0.526

GnomAD4 exome AF: 0.528 AC: 771891 AN: 1461548 Hom.: 204259 Cov.: 59 AF XY: 0.529 AC XY: 384783 AN XY: 727058

African (AFR) AF: 0.483 AC: 16185 AN: 33476

American (AMR) AF: 0.553 AC: 24682 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.525 AC: 13708 AN: 26122

East Asian (EAS) AF: 0.500 AC: 19868 AN: 39700

South Asian (SAS) AF: 0.550 AC: 47416 AN: 86246

European-Finnish (FIN) AF: 0.455 AC: 24314 AN: 53394

Middle Eastern (MID) AF: 0.579 AC: 3337 AN: 5766

European-Non Finnish (NFE) AF: 0.531 AC: 590486 AN: 1111788

Other (OTH) AF: 0.528 AC: 31895 AN: 60388

GnomAD4 genome AF: 0.514 AC: 78128 AN: 152014 Hom.: 20263 Cov.: 33 AF XY: 0.512 AC XY: 38036 AN XY: 74296

African (AFR) AF: 0.484 AC: 20090 AN: 41466

American (AMR) AF: 0.530 AC: 8102 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.523 AC: 1814 AN: 3468

East Asian (EAS) AF: 0.522 AC: 2690 AN: 5156

South Asian (SAS) AF: 0.536 AC: 2583 AN: 4816

European-Finnish (FIN) AF: 0.460 AC: 4865 AN: 10570

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.530 AC: 35980 AN: 67934

Other (OTH) AF: 0.519 AC: 1097 AN: 2112

Alfa AF: 0.509 Hom.: 11861

Bravo AF: 0.523

TwinsUK AF: 0.535 AC: 1985

ALSPAC AF: 0.532 AC: 2051

ESP6500AA AF: 0.493 AC: 2172

ESP6500EA AF: 0.528 AC: 4540

ExAC AF: 0.524 AC: 63630

Asia WGS AF: 0.454 AC: 1579 AN: 3478

EpiCase AF: 0.546

EpiControl AF: 0.548

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	0.052
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.00027	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		4.6
PROVEAN	Pathogenic	-8.2	D
REVEL	Benign	0.17
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.020	D
Polyphen		0.17	B
Vest4		0.43
MPC		0.54
ClinPred		0.087	T
GERP RS		4.3
Varity_R		0.70
gMVP		0.43
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2240695; hg19: chr5-140168151; COSMIC: COSV65373874; COSMIC: COSV65373874;