NM_014822.4:c.697G>C

Variant names:

• chr4-118815132-C-G
• rs730882211
• NM_014822.4:c.697G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_014822.4(SEC24D):​c.697G>C​(p.Gly233Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G233D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SEC24D NM_014822.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 2.40
• Publications: 2 publications found

Genes affected

SEC24D (HGNC:10706): (SEC24 homolog D, 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. This gene product is implicated in the shaping of the vesicle, and also in cargo selection and concentration. Mutations in this gene have been associated with Cole-Carpenter syndrome, a disorder affecting bone formation, resulting in craniofacial malformations and bones that break easily. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

SEC24D Gene-Disease associations (from GenCC):

• Cole-Carpenter syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• Cole-Carpenter syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014822.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC24D	NM_014822.4	MANE Select	c.697G>C	p.Gly233Arg	missense	Exon 6 of 23	NP_055637.2	O94855-1
	SEC24D	NM_001318066.2		c.700G>C	p.Gly234Arg	missense	Exon 6 of 23	NP_001304995.1	O94855-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC24D	ENST00000280551.11	TSL:1 MANE Select	c.697G>C	p.Gly233Arg	missense	Exon 6 of 23	ENSP00000280551.6	O94855-1
	SEC24D	ENST00000509818.5	TSL:1	n.548G>C		non_coding_transcript_exon	Exon 5 of 12	ENSP00000424085.1	D6RBM1
	SEC24D	ENST00000514561.5	TSL:1	n.*671G>C		non_coding_transcript_exon	Exon 7 of 23	ENSP00000422717.1	D6RAE2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461842 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cole-Carpenter syndrome 2 (1)
1	-	-	Seizure;C3714756:Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.0017
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.40		Gain of glycosylation at Y238 (P = 0.0103)
MVP		0.54
MPC		0.75
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.61
gMVP		0.54
Mutation Taster		=13/87	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs730882211; hg19: chr4-119736287; COSMIC: COSV54883195; COSMIC: COSV54883195;