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.

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.1295T>C	p.Val432Ala	missense	Exon 11 of 12	NP_001075955.2
	ACD	NM_022914.3		c.1286T>C	p.Val429Ala	missense	Exon 11 of 12	NP_075065.3
	ACD	NM_001410884.1		c.1208T>C	p.Val403Ala	missense	Exon 10 of 11	NP_001397813.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACD	ENST00000620761.6	TSL:1 MANE Select	c.1295T>C	p.Val432Ala	missense	Exon 11 of 12	ENSP00000478084.1
	ACD	ENST00000695659.1		c.1313T>C	p.Val438Ala	missense	Exon 11 of 12	ENSP00000512089.1
	ACD	ENST00000219251.13	TSL:2	c.1286T>C	p.Val429Ala	missense	Exon 11 of 12	ENSP00000219251.8

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	2	Dyskeratosis congenita, autosomal dominant 6 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.0068	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0000011	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
Polyphen		0.0	B
Vest4		0.058
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;