chr22-30407108-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_012429.5(SEC14L2):​c.188G>A​(p.Arg63Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,732 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 (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

SEC14L2
NM_012429.5 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.75
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SEC14L2NM_012429.5 linkuse as main transcriptc.188G>A p.Arg63Gln missense_variant 4/12 ENST00000615189.5
SEC14L2NM_033382.3 linkuse as main transcriptc.188G>A p.Arg63Gln missense_variant 4/11
SEC14L2NM_001291932.2 linkuse as main transcriptc.26G>A p.Arg9Gln missense_variant 3/11
SEC14L2NM_001204204.3 linkuse as main transcriptc.174+723G>A intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SEC14L2ENST00000615189.5 linkuse as main transcriptc.188G>A p.Arg63Gln missense_variant 4/121 NM_012429.5 P1O76054-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152142
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
251278
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135872
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000424
AC:
62
AN:
1461590
Hom.:
0
Cov.:
31
AF XY:
0.0000413
AC XY:
30
AN XY:
727066
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000522
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152142
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74310
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000847
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 17, 2023The c.188G>A (p.R63Q) alteration is located in exon 4 (coding exon 4) of the SEC14L2 gene. This alteration results from a G to A substitution at nucleotide position 188, causing the arginine (R) at amino acid position 63 to be replaced by a glutamine (Q). 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
Uncertain
0.41
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.74
D;T;.;.;T
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
4.3
H;.;H;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.55
T
PROVEAN
Uncertain
-3.4
.;D;D;D;D
REVEL
Pathogenic
0.69
Sift
Uncertain
0.0030
.;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
1.0
D;.;D;.;.
Vest4
0.98
MutPred
0.91
Gain of ubiquitination at K66 (P = 0.05);.;Gain of ubiquitination at K66 (P = 0.05);.;.;
MVP
0.99
ClinPred
1.0
D
GERP RS
4.5
Varity_R
0.74
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.17
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs774075947; hg19: chr22-30803097; COSMIC: COSV57240624; COSMIC: COSV57240624; API