rs374948412

Variant names:

• chr20-46174905-C-G
• rs374948412
• NM_021248.3:c.2088G>C

Your query was ambiguous. Multiple possible variants found:

• chr20-46174905-C-G
• chr20-46174905-C-A
• chr20-46174905-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021248.3(CDH22):​c.2088G>C​(p.Glu696Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000921 in 1,411,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CDH22 NM_021248.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.56
• Publications: 1 publications found

Genes affected

CDH22 (HGNC:13251): (cadherin 22) This gene is a member of the cadherin superfamily. The gene product is composed of five cadherin repeat domains and a cytoplasmic tail similar to the highly conserved cytoplasmic region of classical cadherins. Expressed predominantly in the brain, this putative calcium-dependent cell adhesion protein may play an important role in morphogenesis and tissue formation in neural and non-neural cells during development and maintenance of the brain and neuroendocrine organs. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0675067).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021248.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH22	NM_021248.3	MANE Select	c.2088G>C	p.Glu696Asp	missense	Exon 12 of 12	NP_067071.1	Q9UJ99

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH22	ENST00000537909.4	TSL:2 MANE Select	c.2088G>C	p.Glu696Asp	missense	Exon 12 of 12	ENSP00000437790.1	Q9UJ99
	CDH22	ENST00000946368.1		c.2088G>C	p.Glu696Asp	missense	Exon 12 of 12	ENSP00000616427.1
	CDH22	ENST00000946370.1		c.2088G>C	p.Glu696Asp	missense	Exon 12 of 12	ENSP00000616429.1

Frequencies

GnomAD3 genomes AF: 0.0000404 AC: 6 AN: 148454 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000284 AC: 5 AN: 175976 AF XY: 0.0000201

Gnomad AFR exome AF: 0.000460

Gnomad AMR exome AF: 0.0000407

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000554 AC: 7 AN: 1263102 Hom.: 0 Cov.: 36 AF XY: 0.00000319 AC XY: 2 AN XY: 626378

African (AFR) AF: 0.000191 AC: 5 AN: 26172

American (AMR) AF: 0.0000308 AC: 1 AN: 32500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20458

East Asian (EAS) AF: 0.00 AC: 0 AN: 23320

South Asian (SAS) AF: 0.00 AC: 0 AN: 72524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4036

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1005988

Other (OTH) AF: 0.0000202 AC: 1 AN: 49496

GnomAD4 genome AF: 0.0000404 AC: 6 AN: 148454 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 1 AN XY: 72382

African (AFR) AF: 0.000147 AC: 6 AN: 40742

American (AMR) AF: 0.00 AC: 0 AN: 14990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 4810

South Asian (SAS) AF: 0.00 AC: 0 AN: 4464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67116

Other (OTH) AF: 0.00 AC: 0 AN: 2054

Alfa AF: 0.0000436 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.000515 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000416 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.65	N
PhyloP100		2.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.10	N
REVEL	Benign	0.079
Sift	Benign	0.27	T
Sift4G	Benign	0.35	T
Polyphen		0.046	B
Vest4		0.16
MutPred		0.42		Loss of sheet (P = 0.0054)
MVP		0.57
ClinPred		0.11	T
GERP RS		3.9
Varity_R		0.11
gMVP		0.56
Mutation Taster		=85/15	polymorphism

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: rs374948412; hg19: chr20-44803544;