3-123271587-C-G

Variant names:

• chr3-123271587-C-G
• rs1262481244
• NM_012430.5:c.789C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012430.5(SEC22A):​c.789C>G​(p.Ile263Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SEC22A NM_012430.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3253079).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEC22A	NM_012430.5	c.789C>G	p.Ile263Met	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.789C>G	p.Ile263Met	missense_variant	Exon 7 of 7	1	NM_012430.5	ENSP00000417972.1
SEC22A	ENST00000309934.4	c.789C>G	p.Ile263Met	missense_variant	Exon 6 of 6	1		ENSP00000310521.4
SEC22A	ENST00000473494.6	c.789C>G	p.Ile263Met	missense_variant	Exon 8 of 8	3		ENSP00000420343.2
SEC22A	ENST00000481965.6	c.*14C>G		3_prime_UTR_variant	Exon 4 of 4	3		ENSP00000420128.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251342 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461844 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.789C>G (p.I263M) alteration is located in exon 7 (coding exon 6) of the SEC22A gene. This alteration results from a C to G substitution at nucleotide position 789, causing the isoleucine (I) at amino acid position 263 to be replaced by a methionine (M). 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	0.30
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T;T
Eigen	Benign	0.041
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.6	M;.;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.88	P;.;P
Vest4		0.67
MutPred		0.32		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.22
MPC		0.29
ClinPred		0.87	D
GERP RS		3.0
Varity_R		0.38
gMVP		0.73

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: rs1262481244; hg19: chr3-122990434;