rs72677221

Variant names:

• chr2-178621869-G-A
• rs72677221
• NM_001267550.2:c.45053C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178621869-G-A
• chr2-178621869-G-T
• chr2-178621869-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.45053C>T​(p.Ala15018Val) variant causes a missense change. The variant allele was found at a frequency of 0.000225 in 1,612,066 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A15018E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00041 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 6.81
• Publications: 4 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008384526).
• BP6: Variant 2-178621869-G-A is Benign according to our data. Variant chr2-178621869-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000408 (62/151984) while in subpopulation AMR AF = 0.00361 (55/15238). AF 95% confidence interval is 0.00285. There are 2 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. 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
	TTN	NM_001267550.2	MANE Select	c.45053C>T	p.Ala15018Val	missense	Exon 244 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.40130C>T	p.Ala13377Val	missense	Exon 194 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.37349C>T	p.Ala12450Val	missense	Exon 193 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.45053C>T	p.Ala15018Val	missense	Exon 244 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.44897C>T	p.Ala14966Val	missense	Exon 242 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.44777C>T	p.Ala14926Val	missense	Exon 242 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 62 AN: 151866 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00368

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000844 AC: 209 AN: 247564 AF XY: 0.000618

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.00560

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000893

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.000206 AC: 301 AN: 1460082 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 118 AN XY: 726320

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00547 AC: 244 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.0000760 AC: 3 AN: 39462

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111038

Other (OTH) AF: 0.000249 AC: 15 AN: 60278

GnomAD4 genome AF: 0.000408 AC: 62 AN: 151984 Hom.: 2 Cov.: 33 AF XY: 0.000458 AC XY: 34 AN XY: 74270

African (AFR) AF: 0.0000964 AC: 4 AN: 41512

American (AMR) AF: 0.00361 AC: 55 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5114

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67916

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000218 Hom.: 1

Bravo AF: 0.000582

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000687 AC: 83

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	0.98
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.5	L
PhyloP100		6.8
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.22
Sift	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.47
MVP		0.36
MPC		0.40
ClinPred		0.039	T
GERP RS		5.8
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs72677221; hg19: chr2-179486596; COSMIC: COSV109431752; COSMIC: COSV109431752;