16-67645535-C-G

Variant names:

• chr16-67645535-C-G
• rs933304286
• NM_001013838.3:c.41-5C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001013838.3(CARMIL2):​c.41-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,442,006 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CARMIL2 NM_001013838.3 splice_region, intron
• Scores: Splicing: ADA: 0.6099
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.556
• 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: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

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=-0.33).
• BP6: Variant 16-67645535-C-G is Benign according to our data. Variant chr16-67645535-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1470895.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.41-5C>G		splice_region intron	N/A	NP_001013860.1	Q6F5E8-1
	CARMIL2	NM_001438835.1		c.41-5C>G		splice_region intron	N/A	NP_001425764.1
	CARMIL2	NM_001438244.1		c.41-5C>G		splice_region intron	N/A	NP_001425173.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARMIL2	ENST00000334583.11	TSL:1 MANE Select	c.41-5C>G		splice_region intron	N/A	ENSP00000334958.5	Q6F5E8-1
	CARMIL2	ENST00000545661.5	TSL:1	c.41-5C>G		splice_region intron	N/A	ENSP00000441481.1	Q6F5E8-2
	CARMIL2	ENST00000696175.1		c.41-5C>G		splice_region intron	N/A	ENSP00000512465.1	A0A8Q3SII9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000459 AC: 1 AN: 217946 AF XY: 0.00000844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000506

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1442006 Hom.: 0 Cov.: 32 AF XY: 0.00000559 AC XY: 4 AN XY: 715740

African (AFR) AF: 0.00 AC: 0 AN: 32990

American (AMR) AF: 0.0000730 AC: 3 AN: 41102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25770

East Asian (EAS) AF: 0.00 AC: 0 AN: 38642

South Asian (SAS) AF: 0.00 AC: 0 AN: 83758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102832

Other (OTH) AF: 0.0000167 AC: 1 AN: 59728

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

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	-0.33
CADD	Benign	15
DANN	Benign	0.93
PhyloP100		0.56
PromoterAI		0.024	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.61
dbscSNV1_RF	Benign	0.26
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.31		Position offset: 5

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

Other links and lift over

dbSNP: rs933304286; hg19: chr16-67679438;