22-30415794-C-T

Position:

• chr22-30415794-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012429.5(SEC14L2):​c.700C>T​(p.Pro234Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SEC14L2 NM_012429.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.09

Genes affected

SEC14L2 (HGNC:10699): (SEC14 like lipid binding 2) This gene encodes a cytosolic protein which belongs to a family of lipid-binding proteins including Sec14p, alpha-tocopherol transfer protein, and cellular retinol-binding protein. The encoded protein stimulates squalene monooxygenase which is a downstream enzyme in the cholesterol biosynthetic pathway. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Oct 2008]

RNF215 (HGNC:33434): (ring finger protein 215) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in Golgi to vacuole transport; protein targeting to vacuole; and ubiquitin-dependent protein catabolic process. Predicted to be integral component of membrane. Predicted to be part of Golgi transport complex. Predicted to be active in endosome; membrane; and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEC14L2	NM_012429.5	c.700C>T	p.Pro234Ser	missense_variant	9/12	ENST00000615189.5
SEC14L2	NM_033382.3	c.700C>T	p.Pro234Ser	missense_variant	9/11
SEC14L2	NM_001291932.2	c.538C>T	p.Pro180Ser	missense_variant	8/11
SEC14L2	NM_001204204.3	c.451C>T	p.Pro151Ser	missense_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEC14L2	ENST00000615189.5	c.700C>T	p.Pro234Ser	missense_variant	9/12	1	NM_012429.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Apr 24, 2023

The c.700C>T (p.P234S) alteration is located in exon 9 (coding exon 9) of the SEC14L2 gene. This alteration results from a C to T substitution at nucleotide position 700, causing the proline (P) at amino acid position 234 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	0.12
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;T;.;.;.;.
Eigen	Benign	0.075
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.9	L;.;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-5.3	.;D;.;D;D;D
REVEL	Uncertain	0.40
Sift	Benign	0.040	.;D;.;D;D;T
Sift4G	Benign	0.086	T;D;T;T;T;D
Polyphen		0.45	B;.;P;B;.;.
Vest4		0.39
MutPred		0.53		Gain of ubiquitination at K230 (P = 0.0804);.;.;Gain of ubiquitination at K230 (P = 0.0804);.;.;
MVP		0.86
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.68
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1934371522; hg19: chr22-30811783;