22-30407128-A-G

Position:

• chr22-30407128-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012429.5(SEC14L2):​c.208A>G​(p.Asn70Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEC14L2 NM_012429.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.41

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24474505).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEC14L2	NM_012429.5	c.208A>G	p.Asn70Asp	missense_variant	4/12	ENST00000615189.5
SEC14L2	NM_033382.3	c.208A>G	p.Asn70Asp	missense_variant	4/11
SEC14L2	NM_001291932.2	c.46A>G	p.Asn16Asp	missense_variant	3/11
SEC14L2	NM_001204204.3	c.174+743A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEC14L2	ENST00000615189.5	c.208A>G	p.Asn70Asp	missense_variant	4/12	1	NM_012429.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jan 09, 2024

The c.208A>G (p.N70D) alteration is located in exon 4 (coding exon 4) of the SEC14L2 gene. This alteration results from a A to G substitution at nucleotide position 208, causing the asparagine (N) at amino acid position 70 to be replaced by an aspartic acid (D). 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	0.098
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;T;.;.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	L;.;L;.;.
MutationTaster	Benign	0.88	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	.;D;N;D;D
REVEL	Benign	0.088
Sift	Benign	0.13	.;T;T;T;T
Sift4G	Benign	0.47	T;T;T;T;T
Polyphen		0.0	B;.;B;.;.
Vest4		0.29
MutPred		0.37		Gain of ubiquitination at K66 (P = 0.0645);.;Gain of ubiquitination at K66 (P = 0.0645);.;.;
MVP		0.73
ClinPred		0.51	D
GERP RS		3.6
Varity_R		0.17
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-30803117;