5-141122904-GA-GAA

Variant names:

• chr5-141122904-G-GA
• rs372292910
• NM_018938.4:c.915dupA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_018938.4(PCDHB4):​c.915dupA​(p.Leu306IlefsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,589,642 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: PCDHB4 NM_018938.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.644
• Publications: 5 publications found

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]

PCDHB@ (HGNC:8679):

ENSG00000272154 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018938.4. 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
	PCDHB4	NM_018938.4	MANE Select	c.915dupA	p.Leu306IlefsTer7	frameshift	Exon 1 of 1	NP_061761.1	Q9Y5E5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHB4	ENST00000194152.4	TSL:6 MANE Select	c.915dupA	p.Leu306IlefsTer7	frameshift	Exon 1 of 1	ENSP00000194152.1	Q9Y5E5
	PCDHB4	ENST00000623478.1	TSL:1	n.214-242dupA		intron	N/A
	ENSG00000272154	ENST00000624802.1	TSL:3	n.365-22150dupT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000530 AC: 8 AN: 151036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000453 AC: 102 AN: 225402 AF XY: 0.000451

Gnomad AFR exome AF: 0.000262

Gnomad AMR exome AF: 0.000513

Gnomad ASJ exome AF: 0.00108

Gnomad EAS exome AF: 0.000175

Gnomad FIN exome AF: 0.000197

Gnomad NFE exome AF: 0.000430

Gnomad OTH exome AF: 0.000561

GnomAD4 exome AF: 0.000236 AC: 339 AN: 1438606 Hom.: 0 Cov.: 34 AF XY: 0.000228 AC XY: 163 AN XY: 715606

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

African (AFR) AF: 0.000217 AC: 7 AN: 32260

American (AMR) AF: 0.000510 AC: 21 AN: 41188

Ashkenazi Jewish (ASJ) AF: 0.000235 AC: 6 AN: 25506

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39588

South Asian (SAS) AF: 0.000360 AC: 30 AN: 83224

European-Finnish (FIN) AF: 0.0000565 AC: 3 AN: 53060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.000224 AC: 246 AN: 1098738

Other (OTH) AF: 0.000286 AC: 17 AN: 59388

⚠️ 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 AF: 0.0000530 AC: 8 AN: 151036 Hom.: 0 Cov.: 32 AF XY: 0.0000407 AC XY: 3 AN XY: 73722

African (AFR) AF: 0.00 AC: 0 AN: 41116

American (AMR) AF: 0.0000659 AC: 1 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67710

Other (OTH) AF: 0.00 AC: 0 AN: 2060

Alfa AF: 0.000633 Hom.: 0

Bravo AF: 0.0000831

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.64
Mutation Taster		=51/149	disease causing

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: rs372292910; hg19: chr5-140502486; COSMIC: COSV52019393; COSMIC: COSV52019393;