chr5-141150948-G-A

Variant names:

• chr5-141150948-G-A
• rs3776096
• NM_018939.4:c.691G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018939.4(PCDHB6):​c.691G>A​(p.Val231Ile) variant causes a missense change. The variant allele was found at a frequency of 0.239 in 1,613,852 control chromosomes in the GnomAD database, including 51,001 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3830 hom., cov: 32)
  • Exomes 𝑓: 0.24 (47171 hom.)
• Consequence: PCDHB6 NM_018939.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.03
• Publications: 38 publications found

Genes affected

PCDHB6 (HGNC:8691): (protocadherin beta 6) 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. Unlike the alpha and gamma clusters, the transcripts from these genes do not share common 3' exons. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell neural connections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

PCDHB@ (HGNC:8679):

ENSG00000280029 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014867485).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018939.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHB6	NM_018939.4	MANE Select	c.691G>A	p.Val231Ile	missense	Exon 1 of 1	NP_061762.2
	PCDHB6	NM_001303145.2		c.283G>A	p.Val95Ile	missense	Exon 2 of 2	NP_001290074.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHB6	ENST00000231136.4	TSL:6 MANE Select	c.691G>A	p.Val231Ile	missense	Exon 1 of 1	ENSP00000231136.1
	PCDHB6	ENST00000622991.1	TSL:2	c.283G>A	p.Val95Ile	missense	Exon 2 of 2	ENSP00000485034.1
	ENSG00000280029	ENST00000624192.1	TSL:5	n.73-13765C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29684 AN: 151910 Hom.: 3831 Cov.: 32

Gnomad AFR AF: 0.0463

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.503

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.210

GnomAD2 exomes AF: 0.270 AC: 67779 AN: 251238 AF XY: 0.272

Gnomad AFR exome AF: 0.0423

Gnomad AMR exome AF: 0.354

Gnomad ASJ exome AF: 0.237

Gnomad EAS exome AF: 0.503

Gnomad FIN exome AF: 0.216

Gnomad NFE exome AF: 0.235

Gnomad OTH exome AF: 0.245

GnomAD4 exome AF: 0.244 AC: 356658 AN: 1461822 Hom.: 47171 Cov.: 36 AF XY: 0.248 AC XY: 180069 AN XY: 727214

African (AFR) AF: 0.0390 AC: 1307 AN: 33480

American (AMR) AF: 0.343 AC: 15325 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 6183 AN: 26134

East Asian (EAS) AF: 0.536 AC: 21282 AN: 39696

South Asian (SAS) AF: 0.340 AC: 29306 AN: 86256

European-Finnish (FIN) AF: 0.216 AC: 11534 AN: 53412

Middle Eastern (MID) AF: 0.184 AC: 1060 AN: 5768

European-Non Finnish (NFE) AF: 0.231 AC: 256620 AN: 1111970

Other (OTH) AF: 0.232 AC: 14041 AN: 60394

GnomAD4 genome AF: 0.195 AC: 29688 AN: 152030 Hom.: 3830 Cov.: 32 AF XY: 0.199 AC XY: 14766 AN XY: 74292

African (AFR) AF: 0.0462 AC: 1916 AN: 41514

American (AMR) AF: 0.264 AC: 4035 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 862 AN: 3470

East Asian (EAS) AF: 0.503 AC: 2579 AN: 5130

South Asian (SAS) AF: 0.325 AC: 1564 AN: 4818

European-Finnish (FIN) AF: 0.206 AC: 2176 AN: 10562

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15886 AN: 67954

Other (OTH) AF: 0.212 AC: 448 AN: 2114

Alfa AF: 0.227 Hom.: 13527

Bravo AF: 0.194

TwinsUK AF: 0.244 AC: 906

ALSPAC AF: 0.229 AC: 884

ESP6500AA AF: 0.0429 AC: 189

ESP6500EA AF: 0.231 AC: 1988

ExAC AF: 0.265 AC: 32162

Asia WGS AF: 0.335 AC: 1165 AN: 3478

EpiCase AF: 0.227

EpiControl AF: 0.233

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.92	T
PhyloP100		5.0
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.045
Sift	Benign	0.17	T
Sift4G	Benign	0.14	T
Vest4		0.086
ClinPred		0.026	T
GERP RS		3.1
gMVP		0.14
Mutation Taster		=92/8	polymorphism (auto)

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: rs3776096; hg19: chr5-140530529; COSMIC: COSV50690938;