17-5486148-C-A

Variant names:

• chr17-5486148-C-A
• rs751485746
• NM_016041.5:c.14G>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_016041.5(DERL2):​c.14G>T​(p.Ser5Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000446 in 1,457,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: DERL2 NM_016041.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.25

Genes affected

DERL2 (HGNC:17943): (derlin 2) Proteins that are unfolded or misfolded in the endoplasmic reticulum (ER) must be refolded or degraded to maintain the homeostasis of the ER. DERL2 is involved in the degradation of misfolded glycoproteins in the ER (Oda et al., 2006 [PubMed 16449189]).[supplied by OMIM, Mar 2008]

MIS12 (HGNC:24967): (MIS12 kinetochore complex component) Involved in attachment of mitotic spindle microtubules to kinetochore and kinetochore assembly. Located in kinetochore and nucleus. Part of MIS12/MIND type complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26137832).
• BS2: High AC in GnomAdExome4 at 65 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DERL2	NM_016041.5	c.14G>T	p.Ser5Ile	missense_variant	Exon 1 of 7	ENST00000158771.9	NP_057125.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DERL2	ENST00000158771.9	c.14G>T	p.Ser5Ile	missense_variant	Exon 1 of 7	1	NM_016041.5	ENSP00000158771.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000287 AC: 7 AN: 243872 Hom.: 0 AF XY: 0.0000376 AC XY: 5 AN XY: 132884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000455

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.0000446 AC: 65 AN: 1457248 Hom.: 0 Cov.: 31 AF XY: 0.0000428 AC XY: 31 AN XY: 724894

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000532

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.14G>T (p.S5I) alteration is located in exon 1 (coding exon 1) of the DERL2 gene. This alteration results from a G to T substitution at nucleotide position 14, causing the serine (S) at amino acid position 5 to be replaced by an isoleucine (I). 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	0.44
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;T;T;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.7	N;.;.;.
REVEL	Benign	0.080
Sift	Uncertain	0.021	D;.;.;.
Sift4G	Uncertain	0.046	D;T;D;D
Polyphen		0.0070	B;.;.;.
Vest4		0.35
MutPred		0.44		Gain of catalytic residue at S5 (P = 0.0037);Gain of catalytic residue at S5 (P = 0.0037);Gain of catalytic residue at S5 (P = 0.0037);Gain of catalytic residue at S5 (P = 0.0037);
MVP		0.28
MPC		0.90
ClinPred		0.24	T
GERP RS		6.2
Varity_R		0.43
gMVP		0.71

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: rs751485746; hg19: chr17-5389468;