rs404639

Variant names:

• chr5-22681345-T-C
• rs404639
• NM_004061.5:c.-523+171713A>G

Variant summary

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

The NM_004061.5(CDH12):​c.-523+171713A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0654 in 151,384 control chromosomes in the GnomAD database, including 627 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.065 (627 hom., cov: 31)
• Consequence: CDH12 NM_004061.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.50
• Publications: 2 publications found

Genes affected

CDH12 (HGNC:1751): (cadherin 12) This gene encodes a type II classical cadherin of the cadherin superfamily. Alternative splicing of this gene results in multiple transcript variants. At least one of these variants encodes a preproprotein that is proteolytically processed to generate the mature cadherin protein. These integral membrane proteins mediate calcium-dependent cell-cell adhesion and are composed of a large N-terminal extracellular domain, a single membrane-spanning domain, and a small, highly conserved C-terminal cytoplasmic domain. Type II (atypical) cadherins are defined based on their lack of a histidine-alanine-valine (HAV) cell adhesion recognition sequence specific to type I cadherins. This particular cadherin appears to be expressed specifically in the brain and its temporal pattern of expression would be consistent with a role during a critical period of neuronal development, perhaps specifically during synaptogenesis. [provided by RefSeq, Nov 2015]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH12	NM_004061.5	c.-523+171713A>G		intron_variant	Intron 1 of 14	ENST00000382254.6	NP_004052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH12	ENST00000382254.6	c.-523+171713A>G		intron_variant	Intron 1 of 14	1	NM_004061.5	ENSP00000371689.1
CDH12	ENST00000504376.6	c.-428+171713A>G		intron_variant	Intron 1 of 13	5		ENSP00000423577.1

Frequencies

GnomAD3 genomes AF: 0.0654 AC: 9898 AN: 151266 Hom.: 625 Cov.: 31

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.0395

Gnomad ASJ AF: 0.0603

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.00790

Gnomad FIN AF: 0.0236

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0291

Gnomad OTH AF: 0.0535

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0654 AC: 9906 AN: 151384 Hom.: 627 Cov.: 31 AF XY: 0.0633 AC XY: 4683 AN XY: 73930

African (AFR) AF: 0.162 AC: 6683 AN: 41152

American (AMR) AF: 0.0394 AC: 597 AN: 15134

Ashkenazi Jewish (ASJ) AF: 0.0603 AC: 209 AN: 3466

East Asian (EAS) AF: 0.000390 AC: 2 AN: 5134

South Asian (SAS) AF: 0.00791 AC: 38 AN: 4806

European-Finnish (FIN) AF: 0.0236 AC: 249 AN: 10530

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0291 AC: 1977 AN: 67860

Other (OTH) AF: 0.0529 AC: 111 AN: 2098

Alfa AF: 0.0521 Hom.: 110

Bravo AF: 0.0722

Asia WGS AF: 0.0140 AC: 51 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Benign	0.75
PhyloP100		3.5
Mutation Taster		=100/0	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: rs404639; hg19: chr5-22681454;