rs1261256

Positions:

• chr5-22454987-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004061.5(CDH12):​c.-427-49636A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 152,060 control chromosomes in the GnomAD database, including 17,353 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 0.47 (17353 hom., cov: 32)
• Consequence: CDH12 NM_004061.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.09

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH12	NM_004061.5	c.-427-49636A>G		intron_variant		ENST00000382254.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH12	ENST00000382254.6	c.-427-49636A>G		intron_variant		1	NM_004061.5	P1
CDH12	ENST00000504376.6	c.-333+50283A>G		intron_variant		5		P1
CDH12	ENST00000520668.1	n.393-49636A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71741 AN: 151942 Hom.: 17341 Cov.: 32

Gnomad AFR AF: 0.438

Gnomad AMI AF: 0.563

Gnomad AMR AF: 0.644

Gnomad ASJ AF: 0.546

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.467

Gnomad OTH AF: 0.515

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

GnomAD4 genome AF: 0.472 AC: 71794 AN: 152060 Hom.: 17353 Cov.: 32 AF XY: 0.471 AC XY: 35005 AN XY: 74306

Gnomad4 AFR AF: 0.438

Gnomad4 AMR AF: 0.644

Gnomad4 ASJ AF: 0.546

Gnomad4 EAS AF: 0.461

Gnomad4 SAS AF: 0.381

Gnomad4 FIN AF: 0.396

Gnomad4 NFE AF: 0.467

Gnomad4 OTH AF: 0.516

Alfa AF: 0.467 Hom.: 7901

Bravo AF: 0.499

Asia WGS AF: 0.416 AC: 1448 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.21
DANN	Benign	0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs1261256; hg19: chr5-22455096;