5-141051823-G-C

Variant names:

• chr5-141051823-G-C
• rs1168348895
• NM_013340.4:c.353G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_013340.4(PCDHB1):​c.353G>C​(p.Arg118Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R118Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PCDHB1 NM_013340.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.532
• Publications: 0 publications found

Genes affected

PCDHB1 (HGNC:8680): (protocadherin beta 1) 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):

PCDHB1-AS1 (HGNC:56111): (PCDHB1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30881304).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013340.4. 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
	PCDHB1	NM_013340.4	MANE Select	c.353G>C	p.Arg118Pro	missense	Exon 1 of 1	NP_037472.2
	PCDHB1-AS1	NR_105056.2		n.357-653C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHB1	ENST00000306549.6	TSL:6 MANE Select	c.353G>C	p.Arg118Pro	missense	Exon 1 of 1	ENSP00000307234.4	Q9Y5F3
	PCDHB1-AS1	ENST00000623109.2	TSL:3	n.480-5257C>G		intron	N/A
	PCDHB1-AS1	ENST00000623741.3	TSL:3	n.295-653C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

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: 39698

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.049	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.53
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.23
Sift	Benign	0.12	T
Sift4G	Benign	0.23	T
Polyphen		0.98	D
Vest4		0.36
MutPred		0.49		Loss of catalytic residue at R118 (P = 0.0528)
MVP		0.67
MPC		1.0
ClinPred		0.94	D
GERP RS		4.9
PromoterAI		-0.038	Neutral
Varity_R		0.64
gMVP		0.70
Mutation Taster		=70/30	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: rs1168348895; hg19: chr5-140431408;