16-22347397-A-T

Variant names:

• chr16-22347397-A-T
• rs747756211
• NM_001802.2:c.933T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001802.2(CDR2):​c.933T>A​(p.Ser311Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDR2 NM_001802.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.436

Genes affected

CDR2 (HGNC:1799): (cerebellar degeneration related protein 2) Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity CDR2_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDR2	NM_001802.2	c.933T>A	p.Ser311Arg	missense_variant	Exon 5 of 5	ENST00000268383.7	NP_001793.1
CDR2	XM_024450143.2	c.708T>A	p.Ser236Arg	missense_variant	Exon 4 of 4		XP_024305911.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDR2	ENST00000268383.7	c.933T>A	p.Ser311Arg	missense_variant	Exon 5 of 5	1	NM_001802.2	ENSP00000268383.2
CDR2	ENST00000564542.5	c.*78T>A		downstream_gene_variant		5		ENSP00000457432.1
CDR2	ENST00000561630.1	n.*679T>A		downstream_gene_variant		5		ENSP00000455915.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251210 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.933T>A (p.S311R) alteration is located in exon 5 (coding exon 5) of the CDR2 gene. This alteration results from a T to A substitution at nucleotide position 933, causing the serine (S) at amino acid position 311 to be replaced by an arginine (R). 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	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	0.033
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.44
MutPred		0.27		Loss of phosphorylation at S311 (P = 0.0029);
MVP		0.87
MPC		0.92
ClinPred		0.95	D
GERP RS		-0.52
Varity_R		0.60

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: rs747756211; hg19: chr16-22358718;