17-73350340-C-T

Variant names:

• chr17-73350340-C-T
• rs139480135
• NM_001144952.2:c.5935G>A

Variant summary

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

The NM_001144952.2(SDK2):​c.5935G>A​(p.Glu1979Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000781 in 1,613,820 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: 𝑓 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: SDK2 NM_001144952.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.51

Genes affected

SDK2 (HGNC:19308): (sidekick cell adhesion molecule 2) The protein encoded by this gene is a member of the immunoglobulin superfamily. The protein contains two immunoglobulin domains and thirteen fibronectin type III domains. Fibronectin type III domains are present in both extracellular and intracellular proteins and tandem repeats are known to contain binding sites for DNA, heparin and the cell surface. This protein, and a homologous mouse sequence, are very similar to the Drosophila sidekick gene product but the specific function of this superfamily member is not yet known. Evidence for alternative splicing at this gene locus has been observed but the full-length nature of additional variants has not yet been determined. [provided by RefSeq, Jul 2008]

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=0.07868165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDK2	NM_001144952.2	c.5935G>A	p.Glu1979Lys	missense_variant	Exon 43 of 45	ENST00000392650.8	NP_001138424.1
SDK2	XM_011524914.3	c.5878G>A	p.Glu1960Lys	missense_variant	Exon 42 of 44		XP_011523216.1
SDK2	XM_011524915.3	c.5935G>A	p.Glu1979Lys	missense_variant	Exon 43 of 46		XP_011523217.1
SDK2	XM_047436313.1	c.5878G>A	p.Glu1960Lys	missense_variant	Exon 42 of 45		XP_047292269.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDK2	ENST00000392650.8	c.5935G>A	p.Glu1979Lys	missense_variant	Exon 43 of 45	5	NM_001144952.2	ENSP00000376421.3
SDK2	ENST00000424778.1	c.3406G>A	p.Glu1136Lys	missense_variant	Exon 25 of 27	5		ENSP00000407098.1
SDK2	ENST00000410094.5	n.1008G>A		non_coding_transcript_exon_variant	Exon 8 of 10	5

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000958 AC: 24 AN: 250522 Hom.: 0 AF XY: 0.0000886 AC XY: 12 AN XY: 135436

Gnomad AFR exome AF: 0.000864

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000486 AC: 71 AN: 1461534 Hom.: 0 Cov.: 38 AF XY: 0.0000344 AC XY: 25 AN XY: 727038

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74460

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000649 Hom.: 0

Bravo AF: 0.000400

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5935G>A (p.E1979K) alteration is located in exon 43 (coding exon 43) of the SDK2 gene. This alteration results from a G to A substitution at nucleotide position 5935, causing the glutamic acid (E) at amino acid position 1979 to be replaced by a lysine (K). 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	0.37
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T;T
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.079	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.091
Sift	Benign	0.12	T;T
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.95	P;.
Vest4		0.65
MVP		0.73
MPC		0.58
ClinPred		0.11	T
GERP RS		5.5
Varity_R		0.22
gMVP		0.29

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: rs139480135; hg19: chr17-71346479;