rs298991

Variant names:

• chr4-118724845-G-A
• rs298991
• NM_014822.4:c.2959-1190C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014822.4(SEC24D):​c.2959-1190C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 152,102 control chromosomes in the GnomAD database, including 31,859 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.64 (31859 hom., cov: 32)
• Consequence: SEC24D NM_014822.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.30
• Publications: 3 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: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEC24D	NM_014822.4	c.2959-1190C>T		intron_variant	Intron 22 of 22	ENST00000280551.11	NP_055637.2
SEC24D	NM_001318066.2	c.2962-1190C>T		intron_variant	Intron 22 of 22		NP_001304995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEC24D	ENST00000280551.11	c.2959-1190C>T		intron_variant	Intron 22 of 22	1	NM_014822.4	ENSP00000280551.6
SEC24D	ENST00000511481.5	c.1852-1190C>T		intron_variant	Intron 15 of 15	1		ENSP00000425491.1
SEC24D	ENST00000502830.1	n.288-1190C>T		intron_variant	Intron 1 of 1	2
SEC24D	ENST00000505134.5	n.3090-1190C>T		intron_variant	Intron 17 of 17	2

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96572 AN: 151984 Hom.: 31835 Cov.: 32

Gnomad AFR AF: 0.441

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.678

Gnomad ASJ AF: 0.632

Gnomad EAS AF: 0.600

Gnomad SAS AF: 0.709

Gnomad FIN AF: 0.774

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.722

Gnomad OTH AF: 0.618

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.635 AC: 96646 AN: 152102 Hom.: 31859 Cov.: 32 AF XY: 0.640 AC XY: 47568 AN XY: 74350

African (AFR) AF: 0.442 AC: 18329 AN: 41474

American (AMR) AF: 0.679 AC: 10373 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 2189 AN: 3466

East Asian (EAS) AF: 0.599 AC: 3093 AN: 5160

South Asian (SAS) AF: 0.711 AC: 3425 AN: 4820

European-Finnish (FIN) AF: 0.774 AC: 8195 AN: 10582

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.722 AC: 49080 AN: 68000

Other (OTH) AF: 0.616 AC: 1299 AN: 2108

Alfa AF: 0.686 Hom.: 46005

Bravo AF: 0.619

Asia WGS AF: 0.630 AC: 2189 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.26
DANN	Benign	0.39
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs298991; hg19: chr4-119646000;