rs14920

chr16-67657612-C-Achr16-67657612-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001082486.2(ACD):c.1371G>T(p.Pro457=) 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 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 criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.72

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]

ACMG classification

Verdict is Benign. Variant got -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]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACD	NM_001082486.2	c.1371G>T	p.Pro457=	synonymous_variant	12/12	ENST00000620761.6
CARMIL2	NM_001013838.3			downstream_gene_variant		ENST00000334583.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACD	ENST00000620761.6	c.1371G>T	p.Pro457=	synonymous_variant	12/12	1	NM_001082486.2	P1
CARMIL2	ENST00000334583.11			downstream_gene_variant		1	NM_001013838.3	A2

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

GnomAD3 exomes AF: 0.0345 AC: 8661 AN: 251346 Hom.: 217 AF XY: 0.0349 AC XY: 4740 AN XY: 135858

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 SAS exome AF: 0.0108

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

Gnomad4 AFR exome AF: 0.00741

Gnomad4 AMR exome AF: 0.0231

Gnomad4 ASJ exome AF: 0.0259

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0109

Gnomad4 FIN exome AF: 0.0524

Gnomad4 NFE exome AF: 0.0517

Gnomad4 OTH exome AF: 0.0426

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

Gnomad4 AFR AF: 0.00943

Gnomad4 AMR AF: 0.0299

Gnomad4 ASJ AF: 0.0308

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.00870

Gnomad4 FIN AF: 0.0532

Gnomad4 NFE AF: 0.0514

Gnomad4 OTH AF: 0.0393

Alfa AF: 0.0449 Hom.: 236

Bravo AF: 0.0317

Asia WGS AF: 0.00779 AC: 28 AN: 3478

EpiCase AF: 0.0504

EpiControl AF: 0.0500

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dyskeratosis congenita, autosomal dominant 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	1.7
Dann	Benign	0.70

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

LitVar

Other links and lift over

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