NM_000061.3:c.718G>C

Variant names:

• chrX-101360626-C-G
• rs128621191
• NM_000061.3:c.718G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000061.3(BTK):​c.718G>C​(p.Glu240Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. E240D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.54
• Publications: 0 publications found

Genes affected

BTK (HGNC:1133): (Bruton tyrosine kinase) The protein encoded by this gene plays a crucial role in B-cell development. Mutations in this gene cause X-linked agammaglobulinemia type 1, which is an immunodeficiency characterized by the failure to produce mature B lymphocytes, and associated with a failure of Ig heavy chain rearrangement. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2013]

BTK Gene-Disease associations (from GenCC):

• Bruton-type agammaglobulinemia

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, ClinGen
• isolated growth hormone deficiency type III

  Inheritance: XL Classification: STRONG, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 90 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. Gene score misZ: 4.0394 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Bruton-type agammaglobulinemia, short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia, isolated growth hormone deficiency type III.
• BP4: Computational evidence support a benign effect (MetaRNN=0.41797996).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000061.3. 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
	BTK	NM_000061.3	MANE Select	c.718G>C	p.Glu240Gln	missense	Exon 8 of 19	NP_000052.1	Q06187-1
	BTK	NM_001287344.2		c.820G>C	p.Glu274Gln	missense	Exon 8 of 19	NP_001274273.1	Q06187-2
	BTK	NM_001287345.2		c.718G>C	p.Glu240Gln	missense	Exon 9 of 17	NP_001274274.1	Q5JY90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTK	ENST00000308731.8	TSL:1 MANE Select	c.718G>C	p.Glu240Gln	missense	Exon 8 of 19	ENSP00000308176.8	Q06187-1
	BTK	ENST00000621635.4	TSL:1	c.820G>C	p.Glu274Gln	missense	Exon 8 of 19	ENSP00000483570.1	Q06187-2
	BTK	ENST00000944957.1		c.718G>C	p.Glu240Gln	missense	Exon 8 of 19	ENSP00000615016.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.092
Sift	Benign	0.054	T
Sift4G	Benign	0.078	T
Polyphen		0.99	D
Vest4		0.34
MutPred		0.38		Gain of methylation at K237 (P = 0.1083)
MVP		0.70
MPC		1.4
ClinPred		0.69	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.54
gMVP		0.86
Mutation Taster		=52/48	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: rs128621191; hg19: chrX-100615614;