rs72648270

Variant names:

• chr2-178539901-T-A
• rs72648270
• NM_001267550.2:c.98164A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178539901-T-A
• chr2-178539901-T-G
• chr2-178539901-T-C

Variant summary

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

The NM_001267550.2(TTN):​c.98164A>T​(p.Ile32722Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,613,844 control chromosomes in the GnomAD database, including 923 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict 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. I32722L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.018 (71 hom., cov: 33)
  • Exomes 𝑓: 0.022 (852 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 3.40
• Publications: 21 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=0.0017301738).
• BP6: Variant 2-178539901-T-A is Benign according to our data. Variant chr2-178539901-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

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.98164A>T	p.Ile32722Phe	missense	Exon 352 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.93241A>T	p.Ile31081Phe	missense	Exon 302 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.90460A>T	p.Ile30154Phe	missense	Exon 301 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.98164A>T	p.Ile32722Phe	missense	Exon 352 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.98008A>T	p.Ile32670Phe	missense	Exon 350 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.97888A>T	p.Ile32630Phe	missense	Exon 350 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2815 AN: 152174 Hom.: 72 Cov.: 33

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0274

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.0353

GnomAD2 exomes AF: 0.0268 AC: 6668 AN: 248794 AF XY: 0.0264

Gnomad AFR exome AF: 0.00362

Gnomad AMR exome AF: 0.0261

Gnomad ASJ exome AF: 0.0221

Gnomad EAS exome AF: 0.157

Gnomad FIN exome AF: 0.00339

Gnomad NFE exome AF: 0.0178

Gnomad OTH exome AF: 0.0290

GnomAD4 exome AF: 0.0220 AC: 32195 AN: 1461552 Hom.: 852 Cov.: 33 AF XY: 0.0217 AC XY: 15801 AN XY: 727068

African (AFR) AF: 0.00406 AC: 136 AN: 33472

American (AMR) AF: 0.0271 AC: 1213 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0227 AC: 593 AN: 26130

East Asian (EAS) AF: 0.164 AC: 6508 AN: 39692

South Asian (SAS) AF: 0.0133 AC: 1149 AN: 86258

European-Finnish (FIN) AF: 0.00313 AC: 167 AN: 53394

Middle Eastern (MID) AF: 0.0761 AC: 439 AN: 5766

European-Non Finnish (NFE) AF: 0.0184 AC: 20484 AN: 1111758

Other (OTH) AF: 0.0249 AC: 1506 AN: 60364

GnomAD4 genome AF: 0.0185 AC: 2812 AN: 152292 Hom.: 71 Cov.: 33 AF XY: 0.0185 AC XY: 1381 AN XY: 74466

African (AFR) AF: 0.00435 AC: 181 AN: 41578

American (AMR) AF: 0.0275 AC: 420 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3468

East Asian (EAS) AF: 0.146 AC: 753 AN: 5164

South Asian (SAS) AF: 0.0126 AC: 61 AN: 4832

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10620

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0177 AC: 1205 AN: 68014

Other (OTH) AF: 0.0345 AC: 73 AN: 2116

Alfa AF: 0.0224 Hom.: 67

Bravo AF: 0.0205

TwinsUK AF: 0.0181 AC: 67

ALSPAC AF: 0.0179 AC: 69

ESP6500AA AF: 0.00384 AC: 15

ESP6500EA AF: 0.0170 AC: 141

ExAC AF: 0.0251 AC: 3031

Asia WGS AF: 0.0570 AC: 199 AN: 3478

EpiCase AF: 0.0227

EpiControl AF: 0.0248

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.83
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.18
Sift	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.41
MPC		0.54
ClinPred		0.024	T
GERP RS		6.2
Mutation Taster		=89/11	polymorphism (auto)

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: rs72648270; hg19: chr2-179404628; COSMIC: COSV104640888; COSMIC: COSV104640888;