rs147431889

Variant names:

• chr1-32274792-C-G
• rs147431889
• NM_005356.5:c.161C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.154
• Publications: 4 publications found

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: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

ACMG classification

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCK	NM_005356.5	MANE Select	c.161C>G	p.Ser54Cys	missense	Exon 3 of 13	NP_005347.3
	LCK	NM_001439146.1		c.161C>G	p.Ser54Cys	missense	Exon 3 of 12	NP_001426075.1
	LCK	NM_001042771.3		c.161C>G	p.Ser54Cys	missense	Exon 3 of 13	NP_001036236.1	P06239-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCK	ENST00000336890.10	TSL:1 MANE Select	c.161C>G	p.Ser54Cys	missense	Exon 3 of 13	ENSP00000337825.5	P06239-1
	LCK	ENST00000333070.4	TSL:1	c.161C>G	p.Ser54Cys	missense	Exon 3 of 13	ENSP00000328213.4	P06239-3
	LCK	ENST00000469765.5	TSL:1	n.220C>G		non_coding_transcript_exon	Exon 3 of 12

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 535 AN: 152112 Hom.: 1 Cov.: 32

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

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.: 3 Cov.: 32 AF XY: 0.000288 AC XY: 209 AN XY: 726844

African (AFR) AF: 0.0106 AC: 356 AN: 33474

American (AMR) AF: 0.00125 AC: 56 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111636

Other (OTH) AF: 0.000961 AC: 58 AN: 60362

GnomAD4 genome AF: 0.00353 AC: 537 AN: 152230 Hom.: 1 Cov.: 32 AF XY: 0.00335 AC XY: 249 AN XY: 74416

African (AFR) AF: 0.0114 AC: 473 AN: 41524

American (AMR) AF: 0.00386 AC: 59 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000983 Hom.: 0

Bravo AF: 0.00445

ESP6500AA AF: 0.00885 AC: 39

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00102 AC: 124

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Severe combined immunodeficiency due to LCK deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.15
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.69	N
REVEL	Benign	0.030
Sift	Benign	0.062	T
Sift4G	Benign	0.11	T
Polyphen		0.0010	B
Vest4		0.18
MVP		0.65
MPC		1.0
ClinPred		0.0076	T
GERP RS		0.76
Varity_R		0.069
gMVP		0.56
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs147431889; hg19: chr1-32740393; COSMIC: COSV107413876; COSMIC: COSV107413876;