rs9972635

chr16-67648677-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001013838.3(CARMIL2):c.1440-8T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0783 in 1,601,826 control chromosomes in the GnomAD database, including 9,627 homozygotes. In-silico tool predicts 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (3188 hom., cov: 32)
  • Exomes 𝑓: 0.071 (6439 hom.)
• Consequence: CARMIL2 NM_001013838.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001198
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.225

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-67648677-T-C is Benign according to our data. Variant chr16-67648677-T-C is described in ClinVar as [Benign]. Clinvar id is 1166790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARMIL2	NM_001013838.3	c.1440-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000334583.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARMIL2	ENST00000334583.11	c.1440-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001013838.3	A2

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22529 AN: 152042 Hom.: 3173 Cov.: 32

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0943

Gnomad ASJ AF: 0.0899

Gnomad EAS AF: 0.00328

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.0360

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.0552

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.0857 AC: 19627 AN: 229068 Hom.: 1674 AF XY: 0.0873 AC XY: 10866 AN XY: 124510

Gnomad AFR exome AF: 0.372

Gnomad AMR exome AF: 0.0533

Gnomad ASJ exome AF: 0.0912

Gnomad EAS exome AF: 0.00234

Gnomad SAS exome AF: 0.171

Gnomad FIN exome AF: 0.0368

Gnomad NFE exome AF: 0.0590

Gnomad OTH exome AF: 0.0790

GnomAD4 exome AF: 0.0709 AC: 102829 AN: 1449666 Hom.: 6439 Cov.: 33 AF XY: 0.0729 AC XY: 52500 AN XY: 720058

Gnomad4 AFR exome AF: 0.396

Gnomad4 AMR exome AF: 0.0565

Gnomad4 ASJ exome AF: 0.0943

Gnomad4 EAS exome AF: 0.00138

Gnomad4 SAS exome AF: 0.161

Gnomad4 FIN exome AF: 0.0386

Gnomad4 NFE exome AF: 0.0570

Gnomad4 OTH exome AF: 0.0887

GnomAD4 genome AF: 0.148 AC: 22577 AN: 152160 Hom.: 3188 Cov.: 32 AF XY: 0.146 AC XY: 10872 AN XY: 74404

Gnomad4 AFR AF: 0.374

Gnomad4 AMR AF: 0.0941

Gnomad4 ASJ AF: 0.0899

Gnomad4 EAS AF: 0.00329

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.0360

Gnomad4 NFE AF: 0.0552

Gnomad4 OTH AF: 0.131

Alfa AF: 0.0709 Hom.: 1116

Bravo AF: 0.157

Asia WGS AF: 0.105 AC: 366 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe combined immunodeficiency due to CARMIL2 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	5.9
Dann	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs9972635; hg19: chr16-67682580;