rs6979

Variant names:

• chr16-67657765-A-G
• rs6979
• NM_001082486.2:c.1295T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001082486.2(ACD):​c.1295T>C​(p.Val432Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 1,613,744 control chromosomes in the GnomAD database, including 209,358 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V432I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.60 (29938 hom., cov: 32)
  • Exomes 𝑓: 0.49 (179420 hom.)
• Consequence: ACD NM_001082486.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.0910
• Publications: 65 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: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0911076E-6).
• BP6: Variant 16-67657765-A-G is Benign according to our data. Variant chr16-67657765-A-G is described in ClinVar as Benign. ClinVar VariationId is 1167321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.885 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACD	NM_001082486.2	c.1295T>C	p.Val432Ala	missense_variant	Exon 11 of 12	ENST00000620761.6	NP_001075955.2
CARMIL2	NM_001013838.3	c.*247A>G		downstream_gene_variant		ENST00000334583.11	NP_001013860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACD	ENST00000620761.6	c.1295T>C	p.Val432Ala	missense_variant	Exon 11 of 12	1	NM_001082486.2	ENSP00000478084.1
CARMIL2	ENST00000334583.11	c.*247A>G		downstream_gene_variant		1	NM_001013838.3	ENSP00000334958.5

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90426 AN: 151964 Hom.: 29887 Cov.: 32

Gnomad AFR AF: 0.893

Gnomad AMI AF: 0.497

Gnomad AMR AF: 0.510

Gnomad ASJ AF: 0.567

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.557

Gnomad FIN AF: 0.525

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.569

GnomAD2 exomes AF: 0.501 AC: 125898 AN: 251212 AF XY: 0.501

Gnomad AFR exome AF: 0.900

Gnomad AMR exome AF: 0.436

Gnomad ASJ exome AF: 0.552

Gnomad EAS exome AF: 0.151

Gnomad FIN exome AF: 0.513

Gnomad NFE exome AF: 0.493

Gnomad OTH exome AF: 0.522

GnomAD4 exome AF: 0.486 AC: 710713 AN: 1461662 Hom.: 179420 Cov.: 62 AF XY: 0.489 AC XY: 355463 AN XY: 727140

African (AFR) AF: 0.910 AC: 30477 AN: 33480

American (AMR) AF: 0.448 AC: 20037 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 14630 AN: 26136

East Asian (EAS) AF: 0.155 AC: 6160 AN: 39700

South Asian (SAS) AF: 0.564 AC: 48647 AN: 86250

European-Finnish (FIN) AF: 0.512 AC: 27294 AN: 53310

Middle Eastern (MID) AF: 0.615 AC: 3547 AN: 5768

European-Non Finnish (NFE) AF: 0.476 AC: 529482 AN: 1111918

Other (OTH) AF: 0.504 AC: 30439 AN: 60384

GnomAD4 genome AF: 0.595 AC: 90532 AN: 152082 Hom.: 29938 Cov.: 32 AF XY: 0.593 AC XY: 44107 AN XY: 74340

African (AFR) AF: 0.893 AC: 37074 AN: 41518

American (AMR) AF: 0.509 AC: 7779 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 1968 AN: 3470

East Asian (EAS) AF: 0.154 AC: 795 AN: 5168

South Asian (SAS) AF: 0.554 AC: 2670 AN: 4820

European-Finnish (FIN) AF: 0.525 AC: 5548 AN: 10572

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.483 AC: 32838 AN: 67948

Other (OTH) AF: 0.574 AC: 1212 AN: 2112

Alfa AF: 0.521 Hom.: 58211

Bravo AF: 0.601

TwinsUK AF: 0.467 AC: 1733

ALSPAC AF: 0.462 AC: 1782

ESP6500AA AF: 0.885 AC: 3889

ESP6500EA AF: 0.489 AC: 4205

ExAC AF: 0.515 AC: 62557

Asia WGS AF: 0.450 AC: 1568 AN: 3478

EpiCase AF: 0.503

EpiControl AF: 0.502

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Dyskeratosis congenita, autosomal dominant 6 Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 68% of patients studied by a panel of primary immunodeficiencies. Number of patients: 65. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.5
DANN	Benign	0.77
DEOGEN2	Benign	0.11	.;T;T;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.0068	N
LIST_S2	Benign	0.21	T;T;.;T;T;.
MetaRNN	Benign	0.0000011	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	.;N;.;.;.;.
PhyloP100		-0.091
PrimateAI	Benign	0.32	T
REVEL	Benign	0.035
Sift4G	Benign	0.93	.;T;T;.;T;.
Polyphen		0.0	.;B;.;.;.;B
Vest4		0.058, 0.086, 0.051
MPC		0.11
ClinPred		0.0080	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.016
gMVP		0.082
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6979; hg19: chr16-67691668; COSMIC: COSV54667315; COSMIC: COSV54667315;