5-141122177-C-T

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.179C>T(p.Ser60Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000841 in 1,614,172 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (2 hom.)
• Consequence: PCDHB4 NM_018938.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.832

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=0.009034723).
• BP6: Variant 5-141122177-C-T is Benign according to our data. Variant chr5-141122177-C-T is described in ClinVar as [Benign]. Clinvar id is 776068.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00472 (719/152290) while in subpopulation AFR AF= 0.0162 (675/41566). AF 95% confidence interval is 0.0152. There are 14 homozygotes in gnomad4. There are 341 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHB4	NM_018938.4	c.179C>T	p.Ser60Phe	missense_variant	1/1	ENST00000194152.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHB4	ENST00000194152.4	c.179C>T	p.Ser60Phe	missense_variant	1/1		NM_018938.4	P1
	ENST00000624802.1	n.365-21422G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 707 AN: 152172 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

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: 0.0000294

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00114 AC: 287 AN: 251392 Hom.: 2 AF XY: 0.000890 AC XY: 121 AN XY: 135902

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000436 AC: 638 AN: 1461882 Hom.: 2 Cov.: 31 AF XY: 0.000358 AC XY: 260 AN XY: 727242

Gnomad4 AFR exome AF: 0.0141

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.00472 AC: 719 AN: 152290 Hom.: 14 Cov.: 32 AF XY: 0.00458 AC XY: 341 AN XY: 74444

Gnomad4 AFR AF: 0.0162

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000703 Hom.: 2

Bravo AF: 0.00517

ESP6500AA AF: 0.0170 AC: 75

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00133 AC: 162

Asia WGS AF: 0.00173 AC: 6 AN: 3478

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	15
Dann	Benign	0.94
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.068	T
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.11
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.028	D
Polyphen		0.027	B
Vest4		0.17
MVP		0.30
ClinPred		0.012	T
GERP RS		2.7
Varity_R		0.16
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: rs35205749; hg19: chr5-140501759;