20-46174889-C-G

Variant names:

• chr20-46174889-C-G
• rs767171662
• NM_021248.3:c.2104G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021248.3(CDH22):​c.2104G>C​(p.Gly702Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000158 in 1,263,412 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: CDH22 NM_021248.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.238
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15418532).

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.2104G>C	p.Gly702Arg	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.2104G>C	p.Gly702Arg	missense	Exon 12 of 12	ENSP00000437790.1	Q9UJ99
	CDH22	ENST00000946368.1		c.2104G>C	p.Gly702Arg	missense	Exon 12 of 12	ENSP00000616427.1
	CDH22	ENST00000946370.1		c.2104G>C	p.Gly702Arg	missense	Exon 12 of 12	ENSP00000616429.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000158 AC: 2 AN: 1263412 Hom.: 0 Cov.: 38 AF XY: 0.00000161 AC XY: 1 AN XY: 619562

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27592

American (AMR) AF: 0.00 AC: 0 AN: 30162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21734

East Asian (EAS) AF: 0.00 AC: 0 AN: 30418

South Asian (SAS) AF: 0.00 AC: 0 AN: 54336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3692

European-Non Finnish (NFE) AF: 0.00000197 AC: 2 AN: 1013130

Other (OTH) AF: 0.00 AC: 0 AN: 51156

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.24
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.13
Sift	Benign	0.12	T
Sift4G	Benign	0.48	T
Polyphen		0.31	B
Vest4		0.20
MutPred		0.47		Gain of solvent accessibility (P = 0.0037)
MVP		0.53
ClinPred		0.71	D
GERP RS		2.9
Varity_R		0.079
gMVP		0.57
Mutation Taster		=80/20	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: rs767171662; hg19: chr20-44803528;