chr5-141246926-G-T

Variant names:

• chr5-141246926-G-T
• rs144325162
• NM_018935.4:c.1348G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018935.4(PCDHB15):​c.1348G>T​(p.Ala450Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000377 in 1,613,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A450T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: PCDHB15 NM_018935.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.732
• Publications: 3 publications found

Genes affected

PCDHB15 (HGNC:8686): (protocadherin beta 15) 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]

PCDHB@ (HGNC:8679):

ENSG00000280029 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.036502868).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHB15	NM_018935.4	c.1348G>T	p.Ala450Ser	missense_variant	Exon 1 of 1	ENST00000231173.6	NP_061758.1
PCDHB@		n.141246926G>T		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDHB15	ENST00000231173.6	c.1348G>T	p.Ala450Ser	missense_variant	Exon 1 of 1	6	NM_018935.4	ENSP00000231173.3
ENSG00000280029	ENST00000726815.1	n.339+713C>A		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 151982 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000290 AC: 73 AN: 251434 AF XY: 0.000294

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000375 AC: 548 AN: 1461278 Hom.: 0 Cov.: 32 AF XY: 0.000400 AC XY: 291 AN XY: 726932

African (AFR) AF: 0.0000299 AC: 1 AN: 33460

American (AMR) AF: 0.000470 AC: 21 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000650 AC: 17 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5284

European-Non Finnish (NFE) AF: 0.000431 AC: 479 AN: 1112004

Other (OTH) AF: 0.000365 AC: 22 AN: 60334

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74356

African (AFR) AF: 0.000145 AC: 6 AN: 41480

American (AMR) AF: 0.00177 AC: 27 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000246 Hom.: 0

Bravo AF: 0.000393

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1348G>T (p.A450S) alteration is located in exon 1 (coding exon 1) of the PCDHB15 gene. This alteration results from a G to T substitution at nucleotide position 1348, causing the alanine (A) at amino acid position 450 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.24	N
PhyloP100		-0.73
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.028
Sift	Uncertain	0.015	D
Sift4G	Benign	0.10	T
Polyphen		0.10	B
Vest4		0.13
MVP		0.24
MPC		0.40
ClinPred		0.017	T
GERP RS		0.13
Varity_R		0.16
gMVP		0.094
Mutation Taster		=94/6	polymorphism

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: rs144325162; hg19: chr5-140626494;