dbSNP rs766580359: LCK:p.Asn211Ser (chr1-32276337-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005356.5(LCK):c.632A>G(p.Asn211Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,423,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N211I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

LCK
NM_005356.5 missense, splice_region

Scores

Splicing: ADA: 0.0007359

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.02

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1624147).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCK	NM_005356.5 link	c.632A>G	p.Asn211Ser	missense_variant, splice_region_variant	Exon 8 of 13	ENST00000336890.10	NP_005347.3	P06239-1A0A0S2Z3Y8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCK	ENST00000336890.10 link	c.632A>G	p.Asn211Ser	missense_variant, splice_region_variant	Exon 8 of 13	1	NM_005356.5	ENSP00000337825.5		P06239-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000211

AC:

AN:

1423532

Hom.:

Cov.:

AF XY:

0.00000283

AC XY:

AN XY:

705666

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32084

American (AMR)

AF:

0.00

AC:

AN:

37746

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23526

East Asian (EAS)

AF:

0.00

AC:

AN:

39374

South Asian (SAS)

AF:

0.00

AC:

AN:

81190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3964

European-Non Finnish (NFE)

AF:

0.00000274

AC:

AN:

1095838

Other (OTH)

AF:

0.00

AC:

AN:

58568

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.21

T;T;.;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.80

.;T;T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.16

T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

0.58

N;N;.;N

PhyloP100

3.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.76

N;.;N;N

REVEL

Benign

0.064

Sift

Benign

0.055

T;.;T;T

Sift4G

Benign

0.52

T;T;T;T

Polyphen

0.0

B;B;.;B

Vest4

0.14

MutPred

0.33

Gain of catalytic residue at N211 (P = 0.0067);Gain of catalytic residue at N211 (P = 0.0067);.;Gain of catalytic residue at N211 (P = 0.0067);

MVP

0.82

MPC

0.71

ClinPred

0.13

GERP RS

3.8

Varity_R

0.27

gMVP

0.64

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00074

dbscSNV1_RF

Benign

0.0020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over