NM_001013838.3:c.42C>T

Variant names:

• chr16-67645541-C-T
• rs1445840219
• NM_001013838.3:c.42C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001013838.3(CARMIL2):​c.42C>T​(p.Gly14Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,446,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CARMIL2 NM_001013838.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.00002922
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.05
• Publications: 0 publications found

Genes affected

CARMIL2 (HGNC:27089): (capping protein regulator and myosin 1 linker 2) This gene encodes a member of the CARMIL (capping protein, Arp2/3, myosin-I linker) family of proteins. The encoded protein interacts with and negatively regulates the heterodimeric capping protein and promotes cell migration. Reduced expression of this gene has been observed in human psoriasis patients. Mutations in this gene cause a human immunodeficiency syndrome characterized by smooth muscle tumors and impaired T-cell function. [provided by RefSeq, May 2017]

CARMIL2 Gene-Disease associations (from GenCC):

• severe combined immunodeficiency due to CARMIL2 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001013838.3. 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
	CARMIL2	NM_001013838.3	MANE Select	c.42C>T	p.Gly14Gly	splice_region synonymous	Exon 2 of 38	NP_001013860.1	Q6F5E8-1
	CARMIL2	NM_001438835.1		c.42C>T	p.Gly14Gly	splice_region synonymous	Exon 2 of 39	NP_001425764.1
	CARMIL2	NM_001438244.1		c.42C>T	p.Gly14Gly	splice_region synonymous	Exon 2 of 39	NP_001425173.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARMIL2	ENST00000334583.11	TSL:1 MANE Select	c.42C>T	p.Gly14Gly	splice_region synonymous	Exon 2 of 38	ENSP00000334958.5	Q6F5E8-1
	CARMIL2	ENST00000545661.5	TSL:1	c.42C>T	p.Gly14Gly	splice_region synonymous	Exon 2 of 38	ENSP00000441481.1	Q6F5E8-2
	CARMIL2	ENST00000696175.1		c.42C>T	p.Gly14Gly	splice_region synonymous	Exon 2 of 39	ENSP00000512465.1	A0A8Q3SII9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1446256 Hom.: 0 Cov.: 32 AF XY: 0.00000278 AC XY: 2 AN XY: 718220

African (AFR) AF: 0.00 AC: 0 AN: 33120

American (AMR) AF: 0.00 AC: 0 AN: 41902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25820

East Asian (EAS) AF: 0.00 AC: 0 AN: 38912

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84234

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1104798

Other (OTH) AF: 0.0000167 AC: 1 AN: 59878

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		-1.0
PromoterAI		-0.012	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.030
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: -1
DS_DG_spliceai		0.90		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1445840219; hg19: chr16-67679444;