chr16-67645283-C-T

Variant names:

• chr16-67645283-C-T
• rs534362264
• NM_001013838.3:c.37C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001013838.3(CARMIL2):​c.37C>T​(p.Arg13*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CARMIL2 NM_001013838.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.137
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 54 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-67645283-C-T is Pathogenic according to our data. Variant chr16-67645283-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1388986.Status of the report is criteria_provided_single_submitter, 1 stars.

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.37C>T	p.Arg13*	stop_gained	Exon 1 of 38	NP_001013860.1	Q6F5E8-1
	CARMIL2	NM_001438835.1		c.37C>T	p.Arg13*	stop_gained	Exon 1 of 39	NP_001425764.1
	CARMIL2	NM_001438244.1		c.37C>T	p.Arg13*	stop_gained	Exon 1 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.37C>T	p.Arg13*	stop_gained	Exon 1 of 38	ENSP00000334958.5	Q6F5E8-1
	CARMIL2	ENST00000545661.5	TSL:1	c.37C>T	p.Arg13*	stop_gained	Exon 1 of 38	ENSP00000441481.1	Q6F5E8-2
	CARMIL2	ENST00000696175.1		c.37C>T	p.Arg13*	stop_gained	Exon 1 of 39	ENSP00000512465.1	A0A8Q3SII9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1451770 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721178

African (AFR) AF: 0.00 AC: 0 AN: 33310

American (AMR) AF: 0.00 AC: 0 AN: 43616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25704

East Asian (EAS) AF: 0.00 AC: 0 AN: 39438

South Asian (SAS) AF: 0.00 AC: 0 AN: 84394

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108008

Other (OTH) AF: 0.00 AC: 0 AN: 59956

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

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_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Uncertain	0.26
Eigen_PC	Benign	-0.020
FATHMM_MKL	Benign	0.19	N
PhyloP100		-0.14
Vest4		0.075
GERP RS		0.29
PromoterAI		0.0064	Neutral

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: rs534362264; hg19: chr16-67679186;