chr1-32276337-A-T

Position:

chr1-32276337-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_005356.5(LCK):c.632A>T(p.Asn211Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000825 in 1,575,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

LCK
NM_005356.5 missense, splice_region

Scores

Splicing: ADA: 0.03589

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.02

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.2503837).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LCK	NM_005356.5 linkuse as main transcript	c.632A>T	p.Asn211Ile	missense_variant, splice_region_variant	8/13	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.632A>T	p.Asn211Ile	missense_variant, splice_region_variant	8/13	1	NM_005356.5	ENSP00000337825.5		P06239-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000182

AC:

AN:

219846

Hom.:

AF XY:

0.0000168

AC XY:

AN XY:

118836

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000142

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000562

AC:

AN:

1423532

Hom.:

Cov.:

AF XY:

0.00000567

AC XY:

AN XY:

705666

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000159

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000183

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Severe combined immunodeficiency due to LCK deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 20, 2021

This sequence change replaces asparagine with isoleucine at codon 211 of the LCK protein (p.Asn211Ile). The asparagine residue is moderately conserved and there is a large physicochemical difference between asparagine and isoleucine. This variant is present in population databases (rs766580359, ExAC 0.009%). This variant has not been reported in the literature in individuals affected with LCK-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Uncertain

0.52

D;D;.;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

.;D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.3

L;L;.;L

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.1

D;.;D;D

REVEL

Benign

0.080

Sift

Uncertain

0.0040

D;.;D;D

Sift4G

Benign

0.11

T;T;D;T

Polyphen

0.0010

B;B;.;B

Vest4

0.43

MutPred

0.33

Loss of disorder (P = 0.0982);Loss of disorder (P = 0.0982);.;Loss of disorder (P = 0.0982);

MVP

0.91

MPC

1.1

ClinPred

0.37

GERP RS

3.8

Varity_R

0.52

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.036

dbscSNV1_RF

Benign

0.15

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