NM_001082486.2:c.1371G>T

Variant names:

• chr16-67657612-C-A
• rs14920
• NM_001082486.2:c.1371G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001082486.2(ACD):​c.1371G>T​(p.Pro457Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.044 in 1,614,150 control chromosomes in the GnomAD database, including 1,817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P457P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.034 (129 hom., cov: 33)
  • Exomes 𝑓: 0.045 (1688 hom.)
• Consequence: ACD NM_001082486.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.72
• Publications: 10 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: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 16-67657612-C-A is Benign according to our data. Variant chr16-67657612-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.72 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0513 is higher than 0.05.

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.1371G>T	p.Pro457Pro	synonymous	Exon 12 of 12	NP_001075955.2	Q96AP0-3
	ACD	NM_022914.3		c.1362G>T	p.Pro454Pro	synonymous	Exon 12 of 12	NP_075065.3	Q96AP0-2
	ACD	NM_001410884.1		c.1284G>T	p.Pro428Pro	synonymous	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.1371G>T	p.Pro457Pro	synonymous	Exon 12 of 12	ENSP00000478084.1	Q96AP0-3
	ACD	ENST00000695659.1		c.1389G>T	p.Pro463Pro	synonymous	Exon 12 of 12	ENSP00000512089.1	A0A8Q3SHY1
	ACD	ENST00000219251.13	TSL:2	c.1362G>T	p.Pro454Pro	synonymous	Exon 12 of 12	ENSP00000219251.8	Q96AP0-2

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5166 AN: 152210 Hom.: 129 Cov.: 33

Gnomad AFR AF: 0.00946

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0300

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.0532

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0514

Gnomad OTH AF: 0.0398

GnomAD2 exomes AF: 0.0345 AC: 8661 AN: 251346 AF XY: 0.0349

Gnomad AFR exome AF: 0.00843

Gnomad AMR exome AF: 0.0216

Gnomad ASJ exome AF: 0.0276

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0501

Gnomad NFE exome AF: 0.0512

Gnomad OTH exome AF: 0.0424

GnomAD4 exome AF: 0.0451 AC: 65931 AN: 1461822 Hom.: 1688 Cov.: 35 AF XY: 0.0442 AC XY: 32120 AN XY: 727212

African (AFR) AF: 0.00741 AC: 248 AN: 33480

American (AMR) AF: 0.0231 AC: 1033 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 678 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0109 AC: 938 AN: 86256

European-Finnish (FIN) AF: 0.0524 AC: 2796 AN: 53370

Middle Eastern (MID) AF: 0.0336 AC: 194 AN: 5768

European-Non Finnish (NFE) AF: 0.0517 AC: 57466 AN: 1111996

Other (OTH) AF: 0.0426 AC: 2575 AN: 60392

GnomAD4 genome AF: 0.0339 AC: 5164 AN: 152328 Hom.: 129 Cov.: 33 AF XY: 0.0332 AC XY: 2470 AN XY: 74480

African (AFR) AF: 0.00943 AC: 392 AN: 41578

American (AMR) AF: 0.0299 AC: 458 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 107 AN: 3472

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.00870 AC: 42 AN: 4826

European-Finnish (FIN) AF: 0.0532 AC: 564 AN: 10608

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0514 AC: 3494 AN: 68036

Other (OTH) AF: 0.0393 AC: 83 AN: 2110

Alfa AF: 0.0445 Hom.: 307

Bravo AF: 0.0317

Asia WGS AF: 0.00779 AC: 28 AN: 3478

EpiCase AF: 0.0504

EpiControl AF: 0.0500

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Dyskeratosis congenita, autosomal dominant 6 (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.7
DANN	Benign	0.70
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs14920; hg19: chr16-67691515; COSMIC: COSV54670775; COSMIC: COSV54670775;