Genetic Variant LCK:p.Thr499Thr (chr1-32285683-G-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_005356.5(LCK):c.1497G>T(p.Thr499Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T499T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LCK
NM_005356.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.13

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: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP7

Synonymous conserved (PhyloP=-4.13 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005356.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LCK	NM_005356.5	MANE Select	c.1497G>T	p.Thr499Thr	synonymous	Exon 13 of 13	NP_005347.3
LCK	NM_001439146.1		c.1671G>T	p.Thr557Thr	synonymous	Exon 12 of 12	NP_001426075.1
LCK	NM_001042771.3		c.1497G>T	p.Thr499Thr	synonymous	Exon 13 of 13	NP_001036236.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LCK	ENST00000336890.10	TSL:1 MANE Select	c.1497G>T	p.Thr499Thr	synonymous	Exon 13 of 13	ENSP00000337825.5
LCK	ENST00000333070.4	TSL:1	c.1587G>T	p.Thr529Thr	synonymous	Exon 13 of 13	ENSP00000328213.4
LCK	ENST00000469765.5	TSL:1	n.1649G>T		non_coding_transcript_exon	Exon 12 of 12

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457116

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724574

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33396

American (AMR)

AF:

0.00

AC:

AN:

43642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26014

East Asian (EAS)

AF:

0.00

AC:

AN:

39526

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53002

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109954

Other (OTH)

AF:

0.00

AC:

AN:

60180

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.36

(source)

DANN

Benign

0.79

PhyloP100

-4.1

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over