rs72648987

Variant names:

• chr2-178715250-G-A
• rs72648987
• NM_001267550.2:c.25936C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178715250-G-A
• chr2-178715250-G-C
• chr2-178715250-G-T

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.25936C>T​(p.Arg8646Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,601,274 control chromosomes in the GnomAD database, including 339 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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. R8646H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (30 hom., cov: 33)
  • Exomes 𝑓: 0.019 (309 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: 0.976
• Publications: 7 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=0.0040379465).
• BP6: Variant 2-178715250-G-A is Benign according to our data. Variant chr2-178715250-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46770.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 = 0.0165 (2517/152128) while in subpopulation AMR AF = 0.025 (382/15270). AF 95% confidence interval is 0.0229. There are 30 homozygotes in GnomAd4. There are 1247 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 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.25936C>T	p.Arg8646Cys	missense	Exon 90 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.24985C>T	p.Arg8329Cys	missense	Exon 88 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.22204C>T	p.Arg7402Cys	missense	Exon 87 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.25936C>T	p.Arg8646Cys	missense	Exon 90 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.25936C>T	p.Arg8646Cys	missense	Exon 90 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.25660C>T	p.Arg8554Cys	missense	Exon 88 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2519 AN: 152010 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.00466

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0250

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.0211

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.0197

GnomAD2 exomes AF: 0.0165 AC: 3945 AN: 239390 AF XY: 0.0167

Gnomad AFR exome AF: 0.00373

Gnomad AMR exome AF: 0.0143

Gnomad ASJ exome AF: 0.0127

Gnomad EAS exome AF: 0.0000572

Gnomad FIN exome AF: 0.0213

Gnomad NFE exome AF: 0.0211

Gnomad OTH exome AF: 0.0202

GnomAD4 exome AF: 0.0191 AC: 27679 AN: 1449146 Hom.: 309 Cov.: 33 AF XY: 0.0191 AC XY: 13747 AN XY: 719772

African (AFR) AF: 0.00324 AC: 106 AN: 32700

American (AMR) AF: 0.0149 AC: 633 AN: 42600

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 310 AN: 25600

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39558

South Asian (SAS) AF: 0.0149 AC: 1250 AN: 83908

European-Finnish (FIN) AF: 0.0229 AC: 1218 AN: 53208

Middle Eastern (MID) AF: 0.0184 AC: 102 AN: 5534

European-Non Finnish (NFE) AF: 0.0208 AC: 23019 AN: 1106328

Other (OTH) AF: 0.0174 AC: 1038 AN: 59710

GnomAD4 genome AF: 0.0165 AC: 2517 AN: 152128 Hom.: 30 Cov.: 33 AF XY: 0.0168 AC XY: 1247 AN XY: 74370

African (AFR) AF: 0.00465 AC: 193 AN: 41528

American (AMR) AF: 0.0250 AC: 382 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 38 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4810

European-Finnish (FIN) AF: 0.0211 AC: 223 AN: 10590

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0228 AC: 1551 AN: 67978

Other (OTH) AF: 0.0195 AC: 41 AN: 2106

Alfa AF: 0.0185 Hom.: 106

Bravo AF: 0.0156

TwinsUK AF: 0.0170 AC: 63

ALSPAC AF: 0.0210 AC: 81

ESP6500AA AF: 0.00625 AC: 23

ESP6500EA AF: 0.0223 AC: 183

ExAC AF: 0.0164 AC: 1983

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0226

EpiControl AF: 0.0218

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	4	not provided (4)
-	-	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	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Benign	0.85
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.98
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.084
Sift	Benign	0.17	T
Polyphen		0.0010	B
Vest4		0.10
MPC		0.11
ClinPred		0.028	T
GERP RS		3.6
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs72648987; hg19: chr2-179579977;