16-67645256-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001013838.3(CARMIL2):c.10A>C(p.Thr4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CARMIL2 NM_001013838.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.414

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06491044).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARMIL2	NM_001013838.3	c.10A>C	p.Thr4Pro	missense_variant	1/38	ENST00000334583.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARMIL2	ENST00000334583.11	c.10A>C	p.Thr4Pro	missense_variant	1/38	1	NM_001013838.3	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448022 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.10A>C (p.T4P) alteration is located in exon 1 (coding exon 1) of the CARMIL2 gene. This alteration results from a A to C substitution at nucleotide position 10, causing the threonine (T) at amino acid position 4 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.023	T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.48	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.065	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.084
Sift	Uncertain	0.016	D;D
Sift4G	Benign	0.074	T;T
Polyphen		0.0010	B;.
Vest4		0.076
MutPred		0.22		Loss of phosphorylation at T4 (P = 0.0069);Loss of phosphorylation at T4 (P = 0.0069);
MVP		0.21
MPC		0.28
ClinPred		0.14	T
GERP RS		3.0
Varity_R		0.30
gMVP		0.33

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-67679159;