5-21752146-T-A

Position:

• chr5-21752146-T-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004061.5(CDH12):​c.1976A>T​(p.His659Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,613,972 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: CDH12 NM_004061.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH12	NM_004061.5	c.1976A>T	p.His659Leu	missense_variant	15/15	ENST00000382254.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH12	ENST00000382254.6	c.1976A>T	p.His659Leu	missense_variant	15/15	1	NM_004061.5	P1
	ENST00000522350.1	n.477-22253T>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000271 AC: 68 AN: 251164 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000189 AC: 276 AN: 1461806 Hom.: 2 Cov.: 34 AF XY: 0.000224 AC XY: 163 AN XY: 727200

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00109

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000139

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74328

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2022

The c.1976A>T (p.H659L) alteration is located in exon 15 (coding exon 11) of the CDH12 gene. This alteration results from a A to T substitution at nucleotide position 1976, causing the histidine (H) at amino acid position 659 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.029	T;T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Uncertain	0.60
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.41	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.77
MVP		0.89
MPC		0.40
ClinPred		0.087	T
GERP RS		5.3
Varity_R		0.38
gMVP		0.81

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: rs143993546; hg19: chr5-21752255;