5-141122128-G-T

Variant summary

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

The NM_018938.4(PCDHB4):c.130G>T(p.Val44Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000469 in 1,614,192 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (3 hom.)
• Consequence: PCDHB4 NM_018938.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.661

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00839293).
• BP6: Variant 5-141122128-G-T is Benign according to our data. Variant chr5-141122128-G-T is described in ClinVar as [Benign]. Clinvar id is 792012.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHB4	NM_018938.4	c.130G>T	p.Val44Leu	missense_variant	1/1	ENST00000194152.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHB4	ENST00000194152.4	c.130G>T	p.Val44Leu	missense_variant	1/1		NM_018938.4	P1
	ENST00000624802.1	n.365-21373C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 375 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00878

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000700 AC: 176 AN: 251472 Hom.: 2 AF XY: 0.000567 AC XY: 77 AN XY: 135916

Gnomad AFR exome AF: 0.00966

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000261 AC: 382 AN: 1461888 Hom.: 3 Cov.: 31 AF XY: 0.000239 AC XY: 174 AN XY: 727242

Gnomad4 AFR exome AF: 0.00983

Gnomad4 AMR exome AF: 0.000514

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: 0.00000270

Gnomad4 OTH exome AF: 0.000430

GnomAD4 genome AF: 0.00246 AC: 375 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74470

Gnomad4 AFR AF: 0.00876

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000335 Hom.: 0

Bravo AF: 0.00295

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000906 AC: 110

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

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.96	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.17
Sift	Benign	0.059	T
Sift4G	Uncertain	0.036	D
Polyphen		0.036	B
Vest4		0.21
MutPred		0.74		Loss of sheet (P = 0.1158);
MVP		0.32
ClinPred		0.019	T
GERP RS		-0.22
Varity_R		0.11
gMVP		0.65

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: rs77188774; hg19: chr5-140501710; COSMIC: COSV52026707; COSMIC: COSV52026707;