16-67657647-G-C

Variant names:

• chr16-67657647-G-C
• rs1050346
• NM_001082486.2:c.1336C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001082486.2(ACD):​c.1336C>G​(p.Leu446Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L446L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACD NM_001082486.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.482
• Publications: 0 publications found

Genes affected

ACD (HGNC:25070): (ACD shelterin complex subunit and telomerase recruitment factor) This gene encodes a protein that is involved in telomere function. This protein is one of six core proteins in the telosome/shelterin telomeric complex, which functions to maintain telomere length and to protect telomere ends. Through its interaction with other components, this protein plays a key role in the assembly and stabilization of this complex, and it mediates the access of telomerase to the telomere. Multiple transcript variants encoding different isoforms have been found for this gene. This gene, which is also referred to as TPP1, is distinct from the unrelated TPP1 gene on chromosome 11, which encodes tripeptidyl-peptidase I. [provided by RefSeq, Jul 2008]

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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08197528).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001082486.2. 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
	ACD	NM_001082486.2	MANE Select	c.1336C>G	p.Leu446Val	missense	Exon 12 of 12	NP_001075955.2	Q96AP0-3
	ACD	NM_022914.3		c.1327C>G	p.Leu443Val	missense	Exon 12 of 12	NP_075065.3	Q96AP0-2
	ACD	NM_001410884.1		c.1249C>G	p.Leu417Val	missense	Exon 11 of 11	NP_001397813.1	A0A8Q3WM11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACD	ENST00000620761.6	TSL:1 MANE Select	c.1336C>G	p.Leu446Val	missense	Exon 12 of 12	ENSP00000478084.1	Q96AP0-3
	ACD	ENST00000695659.1		c.1354C>G	p.Leu452Val	missense	Exon 12 of 12	ENSP00000512089.1	A0A8Q3SHY1
	ACD	ENST00000219251.13	TSL:2	c.1327C>G	p.Leu443Val	missense	Exon 12 of 12	ENSP00000219251.8	Q96AP0-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251276 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461822 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	8.6
DANN	Benign	0.93
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.48
PrimateAI	Benign	0.34	T
REVEL	Benign	0.029
Sift4G	Benign	0.24	T
Polyphen		0.23	B
Vest4		0.22
MutPred		0.22		Loss of helix (P = 0.0626)
MVP		0.45
MPC		0.12
ClinPred		0.063	T
GERP RS		-4.8
Varity_R		0.089
gMVP		0.16

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: rs1050346; hg19: chr16-67691550;