7-3301644-C-G

Position:

• chr7-3301644-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_152744.4(SDK1):​c.58C>G​(p.Pro20Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00531 in 977,122 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (53 hom., cov: 29)
  • Exomes 𝑓: 0.0035 (24 hom.)
• Consequence: SDK1 NM_152744.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.319

Genes affected

SDK1 (HGNC:19307): (sidekick cell adhesion molecule 1) The protein encoded by this gene is a member of the immunoglobulin superfamily. The protein contains six immunoglobulin-like 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

SDK1-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005708307).
• BP6: Variant 7-3301644-C-G is Benign according to our data. Variant chr7-3301644-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2342528.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.016 (2315/144500) while in subpopulation AFR AF= 0.0464 (1874/40384). AF 95% confidence interval is 0.0447. There are 53 homozygotes in gnomad4. There are 1126 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 53 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDK1	NM_152744.4	c.58C>G	p.Pro20Ala	missense_variant	1/45	ENST00000404826.7	NP_689957.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDK1	ENST00000404826.7	c.58C>G	p.Pro20Ala	missense_variant	1/45	1	NM_152744.4	ENSP00000385899.2
SDK1	ENST00000389531.7	c.58C>G	p.Pro20Ala	missense_variant	1/44	5		ENSP00000374182.3
SDK1-AS1	ENST00000437354.1	n.224+585G>C		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2319 AN: 144510 Hom.: 53 Cov.: 29

Gnomad AFR AF: 0.0465

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00867

Gnomad ASJ AF: 0.0113

Gnomad EAS AF: 0.000205

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.000246

Gnomad MID AF: 0.00333

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.0111

GnomAD4 exome AF: 0.00345 AC: 2875 AN: 832622 Hom.: 24 Cov.: 28 AF XY: 0.00337 AC XY: 1295 AN XY: 384558

Gnomad4 AFR exome AF: 0.0461

Gnomad4 AMR exome AF: 0.00305

Gnomad4 ASJ exome AF: 0.0122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0175

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00210

Gnomad4 OTH exome AF: 0.00656

GnomAD4 genome AF: 0.0160 AC: 2315 AN: 144500 Hom.: 53 Cov.: 29 AF XY: 0.0160 AC XY: 1126 AN XY: 70218

Gnomad4 AFR AF: 0.0464

Gnomad4 AMR AF: 0.00860

Gnomad4 ASJ AF: 0.0113

Gnomad4 EAS AF: 0.000205

Gnomad4 SAS AF: 0.0152

Gnomad4 FIN AF: 0.000246

Gnomad4 NFE AF: 0.00275

Gnomad4 OTH AF: 0.0110

Alfa AF: 0.0103 Hom.: 8

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	3.6
DANN	Benign	0.83
DEOGEN2	Benign	0.025	T;T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.44	T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.0057	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.010	N;N;.
REVEL	Benign	0.055
Sift	Pathogenic	0.0	D;D;.
Polyphen		0.56	P;.;.
Vest4		0.12
MVP		0.60
MPC		0.067
ClinPred		0.098	T
GERP RS		1.5
Varity_R		0.064
gMVP		0.062

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: rs867967855; hg19: chr7-3341276;