10-73760803-A-C

Variant names:

• chr10-73760803-A-C
• rs1459039491
• NM_198597.3:c.941A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_198597.3(SEC24C):​c.941A>C​(p.Gln314Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,016 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (1 hom.)
• Consequence: SEC24C NM_198597.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54

Genes affected

SEC24C (HGNC:10705): (SEC24 homolog C, COPII coat complex component) The protein encoded by this gene is a member of the SEC24 subfamily of the SEC23/SEC24 family, which is involved in vesicle trafficking. The encoded protein has similarity to yeast Sec24p component of COPII. COPII is the coat protein complex responsible for vesicle budding from the ER. The product of this gene may play a role in shaping the vesicle, as well as in cargo selection and concentration. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09950948).
• BS2: High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEC24C	NM_198597.3	c.941A>C	p.Gln314Pro	missense_variant	Exon 6 of 23	ENST00000345254.9	NP_940999.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEC24C	ENST00000345254.9	c.941A>C	p.Gln314Pro	missense_variant	Exon 6 of 23	1	NM_198597.3	ENSP00000321845.6

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251358 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461828 Hom.: 1 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727220

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33474

Gnomad4 AMR exome AF: 0.0000895 AC: 4 AN: 44706

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39698

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86246

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53418

Gnomad4 NFE exome AF: 0.00000270 AC: 3 AN: 1111990

Gnomad4 Remaining exome AF: 0.0000662 AC: 4 AN: 60392

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74360

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.000852 AC: 0.000851566 AN: 0.000851566

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.000478 AC: 0.000478469 AN: 0.000478469

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.941A>C (p.Q314P) alteration is located in exon 7 (coding exon 5) of the SEC24C gene. This alteration results from a A to C substitution at nucleotide position 941, causing the glutamine (Q) at amino acid position 314 to be replaced by a proline (P). 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	0.055
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T;T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.75	.;T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.14	N;N;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.3	D;D;.
REVEL	Benign	0.053
Sift	Benign	0.054	T;T;.
Sift4G	Benign	0.14	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.44
MutPred		0.38		Gain of glycosylation at Q314 (P = 0.0013);Gain of glycosylation at Q314 (P = 0.0013);.;
MVP		0.38
MPC		0.53
ClinPred		0.21	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.32
gMVP		0.67
Mutation Taster		=86/14	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

Publications

LitVar

Other links and lift over

dbSNP: rs1459039491; hg19: chr10-75520561;