5-141172924-C-A

Variant names:

• chr5-141172924-C-A
• rs1554279853
• NM_018940.4:c.89C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018940.4(PCDHB7):​c.89C>A​(p.Pro30Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P30L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PCDHB7 NM_018940.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.972
• Publications: 0 publications found

Genes affected

PCDHB7 (HGNC:8692): (protocadherin beta 7) 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. The transcript for this particular family member uses more than one polyadenylation site. [provided by RefSeq, Jul 2008]

PCDHB@ (HGNC:8679):

ENSG00000280029 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042667806).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018940.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHB7	NM_018940.4	MANE Select	c.89C>A	p.Pro30Gln	missense	Exon 1 of 1	NP_061763.1	Q9Y5E2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHB7	ENST00000231137.6	TSL:6 MANE Select	c.89C>A	p.Pro30Gln	missense	Exon 1 of 1	ENSP00000231137.3	Q9Y5E2
	ENSG00000280029	ENST00000624192.1	TSL:5	n.73-35741G>T		intron	N/A
	ENSG00000272154	ENST00000624802.1	TSL:3	n.207-334G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	12
DANN	Benign	0.75
DEOGEN2	Benign	0.0066	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.051	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.12	N
PhyloP100		-0.97
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.022
Sift	Benign	0.14	T
Sift4G	Benign	0.70	T
Polyphen		0.050	B
Vest4		0.12
MutPred		0.38		Gain of sheet (P = 0.1208)
MVP		0.15
MPC		0.13
ClinPred		0.036	T
GERP RS		-0.83
PromoterAI		-0.0020	Neutral
Varity_R		0.040
gMVP		0.089
Mutation Taster		=95/5	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: rs1554279853; hg19: chr5-140552505;