1-32274792-C-G

Position:

chr1-32274792-C-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_005356.5(LCK):c.161C>G(p.Ser54Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00064 in 1,613,434 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 3 hom. )

Consequence

LCK
NM_005356.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.154

Variant links:

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]

LCK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LCK. . Gene score misZ 3.4798 (greater than the threshold 3.09). Trascript score misZ 3.5267 (greater than threshold 3.09). GenCC has associacion of gene with severe combined immunodeficiency due to LCK deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031670034).

BP6

Variant 1-32274792-C-G is Benign according to our data. Variant chr1-32274792-C-G is described in ClinVar as [Benign]. Clinvar id is 541836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LCK	NM_005356.5 linkuse as main transcript	c.161C>G	p.Ser54Cys	missense_variant	3/13	ENST00000336890.10	NP_005347.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LCK	ENST00000336890.10 linkuse as main transcript	c.161C>G	p.Ser54Cys	missense_variant	3/13	1	NM_005356.5	ENSP00000337825	P1	P06239-1

Frequencies

GnomAD3 genomes

AF:

0.00352

AC:

535

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00386

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:

0.00

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000857

AC:

215

AN:

250826

Hom.:

AF XY:

0.000642

AC XY:

AN XY:

135562

show subpopulations

Gnomad AFR exome

AF:

0.0104

Gnomad AMR exome

AF:

0.00101

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:

0.0000176

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000339

AC:

495

AN:

1461204

Hom.:

Cov.:

AF XY:

0.000288

AC XY:

209

AN XY:

726844

show subpopulations

Gnomad4 AFR exome

AF:

0.0106

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.000961

GnomAD4 genome

AF:

0.00353

AC:

537

AN:

152230

Hom.:

Cov.:

AF XY:

0.00335

AC XY:

249

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0114

Gnomad4 AMR

AF:

0.00386

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000983

Hom.:

Bravo

AF:

0.00445

ESP6500AA

AF:

0.00885

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00102

AC:

124

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Severe combined immunodeficiency due to LCK deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.25

T;T;.;T;T;.;T;T;.;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.54

T;.;T;T;T;T;T;T;T;T

MetaRNN

Benign

0.0032

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

.;N;.;.;N;.;.;.;.;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.69

N;N;N;N;.;N;N;N;N;N

REVEL

Benign

0.030

Sift

Benign

0.062

T;D;T;D;.;D;T;D;D;T

Sift4G

Benign

0.11

T;T;T;T;T;T;T;T;D;T

Polyphen

0.0010

B;P;.;.;P;.;.;.;.;P

Vest4

0.18

MVP

0.65

MPC

1.0

ClinPred

0.0076

GERP RS

0.76

Varity_R

0.069

gMVP

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over