5-141122851-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_018938.4(PCDHB4):c.853G>C(p.Asp285His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00593 in 1,613,980 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0042 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (141 hom.)
• Consequence: PCDHB4 NM_018938.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.765

Genes affected

PCDHB4 (HGNC:8689): (protocadherin beta 4) This gene is a member of the protocadherin beta gene cluster, one of three related gene clusters tandemly linked on chromosome five. The gene clusters demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The beta cluster contains 16 genes and 3 pseudogenes, each encoding 6 extracellular cadherin domains and a cytoplasmic tail that deviates from others in the cadherin superfamily. The extracellular domains interact in a homophilic manner to specify differential cell-cell connections. Unlike the alpha and gamma clusters, the transcripts from these genes are made up of only one large exon, not sharing common 3' exons as expected. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins. Their specific functions are unknown but they most likely play a critical role in the establishment and function of specific cell-cell neural connections. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023590326).
• BP6: Variant 5-141122851-G-C is Benign according to our data. Variant chr5-141122851-G-C is described in ClinVar as [Benign]. Clinvar id is 778217.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00424 (646/152258) while in subpopulation SAS AF= 0.0402 (194/4824). AF 95% confidence interval is 0.0356. There are 4 homozygotes in gnomad4. There are 351 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHB4	NM_018938.4	c.853G>C	p.Asp285His	missense_variant	1/1	ENST00000194152.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHB4	ENST00000194152.4	c.853G>C	p.Asp285His	missense_variant	1/1		NM_018938.4	P1
	ENST00000624802.1	n.365-22096C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00425 AC: 646 AN: 152140 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00635

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0402

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00431

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00809 AC: 2028 AN: 250542 Hom.: 36 AF XY: 0.0102 AC XY: 1390 AN XY: 135778

Gnomad AFR exome AF: 0.000446

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00616

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.0418

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00470

Gnomad OTH exome AF: 0.00625

GnomAD4 exome AF: 0.00611 AC: 8931 AN: 1461722 Hom.: 141 Cov.: 34 AF XY: 0.00732 AC XY: 5322 AN XY: 727156

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00608

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0409

Gnomad4 FIN exome AF: 0.00301

Gnomad4 NFE exome AF: 0.00402

Gnomad4 OTH exome AF: 0.00717

GnomAD4 genome AF: 0.00424 AC: 646 AN: 152258 Hom.: 4 Cov.: 32 AF XY: 0.00471 AC XY: 351 AN XY: 74448

Gnomad4 AFR AF: 0.000891

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00635

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0402

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.00431

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00462 Hom.: 3

Bravo AF: 0.00342

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00900 AC: 1092

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.00594

EpiControl AF: 0.00593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.027	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.076
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.16
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.052	T
Polyphen		0.59	P
Vest4		0.13
MVP		0.62
ClinPred		0.077	T
GERP RS		4.4
Varity_R		0.41
gMVP		0.18

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: rs149340599; hg19: chr5-140502433; COSMIC: COSV52023253; COSMIC: COSV52023253;