rs72648970

Variant names:

• chr2-178721877-C-G
• rs72648970
• NM_001267550.2:c.22786G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178721877-C-G
• chr2-178721877-C-A
• chr2-178721877-C-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.22786G>C​(p.Asp7596His) variant causes a missense change. The variant allele was found at a frequency of 0.0338 in 1,612,374 control chromosomes in the GnomAD database, including 1,074 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (62 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1012 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 4.12
• Publications: 12 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=0.0038495064).
• BP6: Variant 2-178721877-C-G is Benign according to our data. Variant chr2-178721877-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0244 (3710/152278) while in subpopulation SAS AF = 0.0479 (231/4820). AF 95% confidence interval is 0.0429. There are 62 homozygotes in GnomAd4. There are 1806 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 62 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.22786G>C	p.Asp7596His	missense	Exon 78 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.21835G>C	p.Asp7279His	missense	Exon 76 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.19054G>C	p.Asp6352His	missense	Exon 75 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.22786G>C	p.Asp7596His	missense	Exon 78 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.22786G>C	p.Asp7596His	missense	Exon 78 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.22510G>C	p.Asp7504His	missense	Exon 76 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0243 AC: 3705 AN: 152160 Hom.: 61 Cov.: 33

Gnomad AFR AF: 0.00535

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0464

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0370

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0283 AC: 7011 AN: 247488 AF XY: 0.0309

Gnomad AFR exome AF: 0.00504

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.0228

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0273

Gnomad NFE exome AF: 0.0369

Gnomad OTH exome AF: 0.0293

GnomAD4 exome AF: 0.0347 AC: 50720 AN: 1460096 Hom.: 1012 Cov.: 32 AF XY: 0.0356 AC XY: 25849 AN XY: 726242

African (AFR) AF: 0.00443 AC: 148 AN: 33428

American (AMR) AF: 0.0129 AC: 576 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.0229 AC: 595 AN: 26026

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39684

South Asian (SAS) AF: 0.0469 AC: 4032 AN: 85958

European-Finnish (FIN) AF: 0.0287 AC: 1530 AN: 53316

Middle Eastern (MID) AF: 0.0379 AC: 218 AN: 5756

European-Non Finnish (NFE) AF: 0.0376 AC: 41767 AN: 1110984

Other (OTH) AF: 0.0307 AC: 1851 AN: 60294

GnomAD4 genome AF: 0.0244 AC: 3710 AN: 152278 Hom.: 62 Cov.: 33 AF XY: 0.0243 AC XY: 1806 AN XY: 74434

African (AFR) AF: 0.00534 AC: 222 AN: 41584

American (AMR) AF: 0.0189 AC: 289 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0479 AC: 231 AN: 4820

European-Finnish (FIN) AF: 0.0261 AC: 277 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0370 AC: 2518 AN: 67996

Other (OTH) AF: 0.0237 AC: 50 AN: 2114

Alfa AF: 0.0335 Hom.: 67

Bravo AF: 0.0218

TwinsUK AF: 0.0361 AC: 134

ALSPAC AF: 0.0337 AC: 130

ESP6500AA AF: 0.00518 AC: 20

ESP6500EA AF: 0.0386 AC: 319

ExAC AF: 0.0291 AC: 3523

Asia WGS AF: 0.0200 AC: 68 AN: 3478

EpiCase AF: 0.0351

EpiControl AF: 0.0357

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Benign	0.91
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.37	T
PhyloP100		4.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.42
Sift	Benign	0.090	T
Polyphen		1.0	D
Vest4		0.11
MPC		0.47
ClinPred		0.025	T
GERP RS		6.2
Mutation Taster		=70/30	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72648970; hg19: chr2-179586604; COSMIC: COSV107420367;