22-30407590-A-G

Position:

• chr22-30407590-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012429.5(SEC14L2):​c.410A>G​(p.His137Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,613,802 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (52 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (42 hom.)
• Consequence: SEC14L2 NM_012429.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.532

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027455986).
• BP6: Variant 22-30407590-A-G is Benign according to our data. Variant chr22-30407590-A-G is described in ClinVar as [Benign]. Clinvar id is 791373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.014 (2134/152248) while in subpopulation AFR AF= 0.0487 (2023/41534). AF 95% confidence interval is 0.0469. There are 52 homozygotes in gnomad4. There are 1019 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 52 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEC14L2	NM_012429.5	c.410A>G	p.His137Arg	missense_variant	5/12	ENST00000615189.5
SEC14L2	NM_033382.3	c.410A>G	p.His137Arg	missense_variant	5/11
SEC14L2	NM_001291932.2	c.248A>G	p.His83Arg	missense_variant	4/11
SEC14L2	NM_001204204.3	c.174+1205A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEC14L2	ENST00000615189.5	c.410A>G	p.His137Arg	missense_variant	5/12	1	NM_012429.5	P1

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2130 AN: 152130 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00385 AC: 965 AN: 250936 Hom.: 24 AF XY: 0.00268 AC XY: 364 AN XY: 135656

Gnomad AFR exome AF: 0.0504

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00151 AC: 2200 AN: 1461554 Hom.: 42 Cov.: 31 AF XY: 0.00130 AC XY: 945 AN XY: 727048

Gnomad4 AFR exome AF: 0.0510

Gnomad4 AMR exome AF: 0.00297

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000115

Gnomad4 OTH exome AF: 0.00336

GnomAD4 genome AF: 0.0140 AC: 2134 AN: 152248 Hom.: 52 Cov.: 32 AF XY: 0.0137 AC XY: 1019 AN XY: 74438

Gnomad4 AFR AF: 0.0487

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00245 Hom.: 13

Bravo AF: 0.0157

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0508 AC: 224

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00450 AC: 546

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 13, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.20
DANN	Benign	0.59
DEOGEN2	Benign	0.051	T;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.024	T;T;T;T
MetaRNN	Benign	0.0027	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.9	N;.;.;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	1.5	.;N;.;N
REVEL	Benign	0.048
Sift	Benign	0.65	.;T;.;T
Sift4G	Benign	0.52	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.063
MVP		0.67
ClinPred		0.0039	T
GERP RS		-4.2
Varity_R		0.15
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs77995868; hg19: chr22-30803579;