2-241030510-C-T

Variant names:

• chr2-241030510-C-T
• rs575768806
• NM_001080437.3:c.440C>T

Variant summary

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

The NM_001080437.3(SNED1):​c.440C>T​(p.Thr147Ile) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T147N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SNED1 NM_001080437.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53

Genes affected

SNED1 (HGNC:24696): (sushi, nidogen and EGF like domains 1) Predicted to enable Notch binding activity. Predicted to be involved in cell-matrix adhesion. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

SNED1-AS1 (HGNC:41060): (SNED1 antisense RNA 1)

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 rank	MANE	Protein	UniProt
SNED1	NM_001080437.3	c.440C>T	p.Thr147Ile	missense_variant	Exon 2 of 32	ENST00000310397.13	NP_001073906.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNED1	ENST00000310397.13	c.440C>T	p.Thr147Ile	missense_variant	Exon 2 of 32	5	NM_001080437.3	ENSP00000308893.8
SNED1	ENST00000405547.7	c.440C>T	p.Thr147Ile	missense_variant	Exon 2 of 30	5		ENSP00000386007.3
SNED1	ENST00000401884.5	c.440C>T	p.Thr147Ile	missense_variant	Exon 2 of 27	5		ENSP00000384871.1
SNED1-AS1	ENST00000458377.1	n.140+2991G>A		intron_variant	Intron 2 of 2	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248650 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135096

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.440C>T (p.T147I) alteration is located in exon 2 (coding exon 2) of the SNED1 gene. This alteration results from a C to T substitution at nucleotide position 440, causing the threonine (T) at amino acid position 147 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	Benign	0.25
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;.;T
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.8	M;M;M
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.99	.;.;D
Vest4		0.52
MutPred		0.56		Loss of catalytic residue at F150 (P = 0.0725);Loss of catalytic residue at F150 (P = 0.0725);Loss of catalytic residue at F150 (P = 0.0725);
MVP		0.66
MPC		0.51
ClinPred		0.79	D
GERP RS		3.5
Varity_R		0.13
gMVP		0.68

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: rs575768806; hg19: chr2-241969927;