2-223598351-A-T

Variant names:

• chr2-223598351-A-T
• rs986919831
• NM_003469.5:c.932T>A

Variant summary

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

The NM_003469.5(SCG2):​c.932T>A​(p.Ile311Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,730 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SCG2 NM_003469.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.91

Genes affected

SCG2 (HGNC:10575): (secretogranin II) The protein encoded by this gene is a member of the chromogranin/secretogranin family of neuroendocrine secretory proteins. Studies in rodents suggest that the full-length protein, secretogranin II, is involved in the packaging or sorting of peptide hormones and neuropeptides into secretory vesicles. The full-length protein is cleaved to produce the active peptide secretoneurin, which exerts chemotaxic effects on specific cell types, and EM66, whose function is unknown. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCG2	NM_003469.5	c.932T>A	p.Ile311Asn	missense_variant	Exon 2 of 2	ENST00000305409.3	NP_003460.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCG2	ENST00000305409.3	c.932T>A	p.Ile311Asn	missense_variant	Exon 2 of 2	1	NM_003469.5	ENSP00000304133.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461730 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.932T>A (p.I311N) alteration is located in exon 2 (coding exon 1) of the SCG2 gene. This alteration results from a T to A substitution at nucleotide position 932, causing the isoleucine (I) at amino acid position 311 to be replaced by an asparagine (N). 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	0.41
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.23
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.79	P
Vest4		0.55
MutPred		0.49		Gain of disorder (P = 0.0098);
MVP		0.24
MPC		0.44
ClinPred		0.91	D
GERP RS		5.6
Varity_R		0.29
gMVP		0.23

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: rs986919831; hg19: chr2-224463069;