rs72677243

Variant names:

• chr2-178614561-A-G
• rs72677243
• NM_001267550.2:c.48953T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178614561-A-G
• chr2-178614561-A-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001267550.2(TTN):​c.48953T>C​(p.Ile16318Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,612,356 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I16318L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (8 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:14
• Conservation: PhyloP100: 9.19
• Publications: 10 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008417815).
• BP6: Variant 2-178614561-A-G is Benign according to our data. Variant chr2-178614561-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47025.
• BS2: High Homozygotes in GnomAdExome4 at 8 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.48953T>C	p.Ile16318Thr	missense	Exon 261 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.44030T>C	p.Ile14677Thr	missense	Exon 211 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.41249T>C	p.Ile13750Thr	missense	Exon 210 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.48953T>C	p.Ile16318Thr	missense	Exon 261 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.48797T>C	p.Ile16266Thr	missense	Exon 259 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.48677T>C	p.Ile16226Thr	missense	Exon 259 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000955 AC: 145 AN: 151794 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000789

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00122 AC: 302 AN: 247762 AF XY: 0.00127

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00997

Gnomad EAS exome AF: 0.0000565

Gnomad FIN exome AF: 0.0000931

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00104 AC: 1513 AN: 1460444 Hom.: 8 Cov.: 34 AF XY: 0.00108 AC XY: 786 AN XY: 726532

African (AFR) AF: 0.000269 AC: 9 AN: 33396

American (AMR) AF: 0.00119 AC: 53 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00954 AC: 249 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39468

South Asian (SAS) AF: 0.000592 AC: 51 AN: 86216

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53358

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5754

European-Non Finnish (NFE) AF: 0.000958 AC: 1065 AN: 1111234

Other (OTH) AF: 0.00124 AC: 75 AN: 60294

GnomAD4 genome AF: 0.000941 AC: 143 AN: 151912 Hom.: 0 Cov.: 32 AF XY: 0.000984 AC XY: 73 AN XY: 74216

African (AFR) AF: 0.000217 AC: 9 AN: 41502

American (AMR) AF: 0.000788 AC: 12 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00110 AC: 75 AN: 67888

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.00151 Hom.: 3

Bravo AF: 0.000948

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00182 AC: 15

ExAC AF: 0.00122 AC: 148

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00224

EpiControl AF: 0.00237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	1	4	not specified (5)
-	-	2	Cardiomyopathy (2)
-	1	1	Tibial muscular dystrophy (2)
-	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	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	20
DANN	Benign	0.85
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0084	T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		9.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D
Polyphen		0.99	D
Vest4		0.54
MVP		0.87
MPC		0.45
ClinPred		0.40	T
GERP RS		5.6
Mutation Taster		=95/5	polymorphism

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: rs72677243; hg19: chr2-179479288; COSMIC: COSV60286115; COSMIC: COSV60286115;