rs11567841

Positions:

chr1-32276033-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_005356.5(LCK):c.601G>A(p.Gly201Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,613,996 control chromosomes in the GnomAD database, including 3 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0018 ( 3 hom. )

Consequence

LCK
NM_005356.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.94

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:

LCK (HGNC:):

LCK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 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=0.010018915).

BP6

Variant 1-32276033-G-A is Benign according to our data. Variant chr1-32276033-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 569666.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr1-32276033-G-A is described in Lovd as [Likely_benign].

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.601G>A	p.Gly201Ser	missense_variant	7/13	ENST00000336890.10	NP_005347.3	P06239-1A0A0S2Z3Y8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LCK	ENST00000336890.10 linkuse as main transcript	c.601G>A	p.Gly201Ser	missense_variant	7/13	1	NM_005356.5	ENSP00000337825.5		P06239-1

Frequencies

GnomAD3 genomes

AF:

0.00111

AC:

169

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000653

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00197

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00109

AC:

273

AN:

251398

Hom.:

AF XY:

0.00107

AC XY:

145

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00219

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00184

AC:

2697

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

1284

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.000580

Gnomad4 NFE exome

AF:

0.00233

Gnomad4 OTH exome

AF:

0.000811

GnomAD4 genome

AF:

0.00111

AC:

169

AN:

152134

Hom.:

Cov.:

AF XY:

0.000928

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.000651

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000566

Gnomad4 NFE

AF:

0.00197

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00173

Hom.:

Bravo

AF:

0.000997

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00101

AC:

123

EpiCase

AF:

0.00180

EpiControl

AF:

0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Severe combined immunodeficiency due to LCK deficiency

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	LCK NM_001042771.2 exon 7 p.Gly201Ser (c.601G>A): This variant has not been reported in the literature but is present in 0.2% (273/129110) of European alleles, including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-32741634-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:569666). This variant amino acid Serine (Ser) is present in >25 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. Of note, although this variant occurs in the exon, splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

LCK-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.45

DEOGEN2

Benign

0.39

T;T;T;T;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.85

T;.;T;T;D;T

M_CAP

Benign

0.055

MetaRNN

Benign

0.010

T;T;T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

-2.7

.;N;.;N;.;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

2.2

N;N;N;.;N;N

REVEL

Benign

0.14

Sift

Benign

1.0

T;T;T;.;T;T

Sift4G

Benign

0.92

T;T;T;T;T;T

Polyphen

0.0050

B;B;.;B;.;B

Vest4

0.13

MVP

0.58

MPC

0.89

ClinPred

0.0049

GERP RS

3.4

Varity_R

0.12

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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