rs145088108

chr1-32274765-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_005356.5(LCK):c.134G>A(p.Arg45Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00436 in 1,607,346 control chromosomes in the GnomAD database, including 456 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (118 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (338 hom.)
• Consequence: LCK NM_005356.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.32

Genes affected

LCK (HGNC:6524): (LCK proto-oncogene, Src family tyrosine kinase) This gene is a member of the Src family of protein tyrosine kinases (PTKs). The encoded protein is a key signaling molecule in the selection and maturation of developing T-cells. It contains N-terminal sites for myristylation and palmitylation, a PTK domain, and SH2 and SH3 domains which are involved in mediating protein-protein interactions with phosphotyrosine-containing and proline-rich motifs, respectively. The protein localizes to the plasma membrane and pericentrosomal vesicles, and binds to cell surface receptors, including CD4 and CD8, and other signaling molecules. Multiple alternatively spliced variants encoding different isoforms have been described. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LCK
• BP4: Computational evidence support a benign effect (MetaRNN=0.0014267564).
• BP6: Variant 1-32274765-G-A is Benign according to our data. Variant chr1-32274765-G-A is described in ClinVar as [Benign]. Clinvar id is 474985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.098 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LCK	NM_005356.5	c.134G>A	p.Arg45Gln	missense_variant	3/13	ENST00000336890.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCK	ENST00000336890.10	c.134G>A	p.Arg45Gln	missense_variant	3/13	1	NM_005356.5	P1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1683 AN: 152024 Hom.: 115 Cov.: 32

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.0155 AC: 3821 AN: 246356 Hom.: 238 AF XY: 0.0119 AC XY: 1576 AN XY: 132926

Gnomad AFR exome AF: 0.00179

Gnomad AMR exome AF: 0.108

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: 0.0000359

Gnomad OTH exome AF: 0.0143

GnomAD4 exome AF: 0.00365 AC: 5313 AN: 1455204 Hom.: 338 Cov.: 32 AF XY: 0.00315 AC XY: 2281 AN XY: 723146

Gnomad4 AFR exome AF: 0.00141

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000244

Gnomad4 OTH exome AF: 0.00537

GnomAD4 genome AF: 0.0112 AC: 1699 AN: 152142 Hom.: 118 Cov.: 32 AF XY: 0.0126 AC XY: 938 AN XY: 74390

Gnomad4 AFR AF: 0.00198

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.00108 Hom.: 8

Bravo AF: 0.0186

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0111 AC: 1353

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe combined immunodeficiency due to LCK deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;.;T;T;.;T;T;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D;.;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0014	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.96	N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.31	N;N;N;N;.;N;N;N;N;N
REVEL	Benign	0.093
Sift	Benign	0.16	T;T;T;T;.;T;T;D;T;T
Sift4G	Benign	0.62	T;T;T;T;T;T;T;D;T;T
Polyphen		0.068	B;B;.;.;B;.;.;.;.;B
Vest4		0.26
MPC		1.0
ClinPred		0.0094	T
GERP RS		3.7
Varity_R		0.080
gMVP		0.38

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: rs145088108; hg19: chr1-32740366;