10-73759752-G-A

Position:

• chr10-73759752-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_198597.3(SEC24C):​c.439G>A​(p.Gly147Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000863 in 1,606,298 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (1 hom.)
• Consequence: SEC24C NM_198597.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.033474088).
• BS2: High AC in GnomAd4 at 84 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEC24C	NM_198597.3	c.439G>A	p.Gly147Ser	missense_variant	4/23	ENST00000345254.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEC24C	ENST00000345254.9	c.439G>A	p.Gly147Ser	missense_variant	4/23	1	NM_198597.3	P1
SEC24C	ENST00000465076.5	c.439G>A	p.Gly147Ser	missense_variant, NMD_transcript_variant	4/22	1
SEC24C	ENST00000339365.2	c.439G>A	p.Gly147Ser	missense_variant	5/24	5		P1
SEC24C	ENST00000635550.1	c.303G>A	p.Ala101=	synonymous_variant, NMD_transcript_variant	3/23	2

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00110

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000395 AC: 96 AN: 242952 Hom.: 0 AF XY: 0.000342 AC XY: 45 AN XY: 131642

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000615

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: 0.000802

Gnomad OTH exome AF: 0.000848

GnomAD4 exome AF: 0.000895 AC: 1302 AN: 1454088 Hom.: 1 Cov.: 32 AF XY: 0.000828 AC XY: 599 AN XY: 723494

Gnomad4 AFR exome AF: 0.000241

Gnomad4 AMR exome AF: 0.0000468

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.0000352

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00109

Gnomad4 OTH exome AF: 0.00115

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74364

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000773 Hom.: 0

Bravo AF: 0.000612

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000461 AC: 56

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2021

The c.439G>A (p.G147S) alteration is located in exon 5 (coding exon 3) of the SEC24C gene. This alteration results from a G to A substitution at nucleotide position 439, causing the glycine (G) at amino acid position 147 to be replaced by a serine (S). 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	0.074
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.031	T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	0.0087
FATHMM_MKL	Benign	0.65	D
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.86	D;D;D;D;D;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.74	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.52	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.027	B;B
Vest4		0.15
MVP		0.83
MPC		0.012
ClinPred		0.041	T
GERP RS		4.9
Varity_R		0.064
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs143287549; hg19: chr10-75519510;