rs995178

Variant names:

• chr5-22446105-A-G
• rs995178
• NM_004061.5:c.-427-40754T>C

Variant summary

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

The NM_004061.5(CDH12):​c.-427-40754T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 151,750 control chromosomes in the GnomAD database, including 16,848 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 (16848 hom., cov: 31)
• Consequence: CDH12 NM_004061.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.43
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.629 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH12	NM_004061.5	c.-427-40754T>C		intron_variant	Intron 2 of 14	ENST00000382254.6	NP_004052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH12	ENST00000382254.6	c.-427-40754T>C		intron_variant	Intron 2 of 14	1	NM_004061.5	ENSP00000371689.1
CDH12	ENST00000504376.6	c.-333+59165T>C		intron_variant	Intron 2 of 13	5		ENSP00000423577.1
CDH12	ENST00000520668.1	n.393-40754T>C		intron_variant	Intron 2 of 3	4

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70656 AN: 151630 Hom.: 16838 Cov.: 31

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.555

Gnomad AMR AF: 0.640

Gnomad ASJ AF: 0.523

Gnomad EAS AF: 0.463

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.507

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

GnomAD4 genome AF: 0.466 AC: 70706 AN: 151750 Hom.: 16848 Cov.: 31 AF XY: 0.465 AC XY: 34440 AN XY: 74134

African (AFR) AF: 0.442 AC: 18265 AN: 41366

American (AMR) AF: 0.640 AC: 9729 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.523 AC: 1812 AN: 3462

East Asian (EAS) AF: 0.461 AC: 2370 AN: 5138

South Asian (SAS) AF: 0.379 AC: 1823 AN: 4814

European-Finnish (FIN) AF: 0.378 AC: 3982 AN: 10526

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 30989 AN: 67930

Other (OTH) AF: 0.508 AC: 1071 AN: 2110

Alfa AF: 0.474 Hom.: 71075

Bravo AF: 0.494

Asia WGS AF: 0.413 AC: 1439 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.13
DANN	Benign	0.47
PhyloP100		-1.4
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: rs995178; hg19: chr5-22446214;