3-123271680-G-C

Variant names:

• chr3-123271680-G-C
• rs757083780
• NM_012430.5:c.882G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012430.5(SEC22A):​c.882G>C​(p.Trp294Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SEC22A NM_012430.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01

Genes affected

SEC22A (HGNC:20260): (SEC22 homolog A, vesicle trafficking protein) The protein encoded by this gene belongs to the member of the SEC22 family of vesicle trafficking proteins. This protein has similarity to rat SEC22 and may act in the early stages of the secretory pathway. [provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18020925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEC22A	NM_012430.5	c.882G>C	p.Trp294Cys	missense_variant	Exon 7 of 7	ENST00000492595.6	NP_036562.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEC22A	ENST00000492595.6	c.882G>C	p.Trp294Cys	missense_variant	Exon 7 of 7	1	NM_012430.5	ENSP00000417972.1
SEC22A	ENST00000309934.4	c.882G>C	p.Trp294Cys	missense_variant	Exon 6 of 6	1		ENSP00000310521.4
SEC22A	ENST00000481965.6	c.*107G>C		3_prime_UTR_variant	Exon 4 of 4	3		ENSP00000420128.2
SEC22A	ENST00000473494.6	c.*16G>C		downstream_gene_variant		3		ENSP00000420343.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.882G>C (p.W294C) alteration is located in exon 7 (coding exon 6) of the SEC22A gene. This alteration results from a G to C substitution at nucleotide position 882, causing the tryptophan (W) at amino acid position 294 to be replaced by a cysteine (C). 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	Benign	0.17
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.030	T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.38	N;N
REVEL	Benign	0.067
Sift	Uncertain	0.028	D;D
Sift4G	Benign	0.18	T;T
Polyphen		0.93	P;P
Vest4		0.60
MutPred		0.40		Gain of catalytic residue at L295 (P = 0.0101);Gain of catalytic residue at L295 (P = 0.0101);
MVP		0.043
MPC		0.17
ClinPred		0.54	D
GERP RS		5.0
Varity_R		0.10
gMVP		0.71

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: rs757083780; hg19: chr3-122990527;