rs147431889

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S54A) has been classified as Uncertain significance.

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

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

severe combined immunodeficiency due to LCK deficiency
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet

LCK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 VariationId is 541836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00353 (537/152230) while in subpopulation AFR AF = 0.0114 (473/41524). AF 95% confidence interval is 0.0105. There are 1 homozygotes in GnomAd4. There are 249 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCK	NM_005356.5 link	c.161C>G	p.Ser54Cys	missense_variant	Exon 3 of 13	ENST00000336890.10	NP_005347.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCK	ENST00000336890.10 link	c.161C>G	p.Ser54Cys	missense_variant	Exon 3 of 13	1	NM_005356.5	ENSP00000337825.5

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

GnomAD2 exomes

AF:

0.000857

AC:

215

AN:

250826

AF XY:

0.000642

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 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

African (AFR)

AF:

0.0106

AC:

356

AN:

33474

American (AMR)

AF:

0.00125

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26040

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1111636

Other (OTH)

AF:

0.000961

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

120

150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00353

AC:

537

AN:

152230

Hom.:

Cov.:

AF XY:

0.00335

AC XY:

249

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0114

AC:

473

AN:

41524

American (AMR)

AF:

0.00386

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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

(source)

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

0.0

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

PhyloP100

0.15

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

Vest4

0.18

ClinPred

0.0076

GERP RS

0.76

Varity_R

0.069

gMVP

0.56

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over