chr2-178578057-C-G

Variant names:

• chr2-178578057-C-G
• rs72646880
• NM_001267550.2:c.68458G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.68458G>C​(p.Ala22820Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,613,208 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A22820A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (5 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:15 O:1
• Conservation: PhyloP100: 7.86
• Publications: 18 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017355025).
• BP6: Variant 2-178578057-C-G is Benign according to our data. Variant chr2-178578057-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47268.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00158 (241/152180) while in subpopulation NFE AF = 0.00252 (171/67974). AF 95% confidence interval is 0.00221. There are 0 homozygotes in GnomAd4. There are 110 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.68458G>C	p.Ala22820Pro	missense	Exon 322 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.63535G>C	p.Ala21179Pro	missense	Exon 272 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.60754G>C	p.Ala20252Pro	missense	Exon 271 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.68458G>C	p.Ala22820Pro	missense	Exon 322 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.68302G>C	p.Ala22768Pro	missense	Exon 320 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.68182G>C	p.Ala22728Pro	missense	Exon 320 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 241 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00252

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00191 AC: 474 AN: 248062 AF XY: 0.00204

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.00518

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.00251

Gnomad OTH exome AF: 0.00332

GnomAD4 exome AF: 0.00189 AC: 2761 AN: 1461028 Hom.: 5 Cov.: 35 AF XY: 0.00196 AC XY: 1422 AN XY: 726790

African (AFR) AF: 0.000598 AC: 20 AN: 33432

American (AMR) AF: 0.000760 AC: 34 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00674 AC: 176 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.00274 AC: 236 AN: 86218

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53370

Middle Eastern (MID) AF: 0.00417 AC: 24 AN: 5760

European-Non Finnish (NFE) AF: 0.00189 AC: 2104 AN: 1111492

Other (OTH) AF: 0.00247 AC: 149 AN: 60342

GnomAD4 genome AF: 0.00158 AC: 241 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.00148 AC XY: 110 AN XY: 74382

African (AFR) AF: 0.000361 AC: 15 AN: 41552

American (AMR) AF: 0.000852 AC: 13 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4826

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00252 AC: 171 AN: 67974

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00233 Hom.: 0

Bravo AF: 0.00153

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000264 AC: 1

ESP6500EA AF: 0.00315 AC: 26

ExAC AF: 0.00195 AC: 236

Asia WGS AF: 0.00173 AC: 6 AN: 3476

EpiCase AF: 0.00344

EpiControl AF: 0.00338

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)
-	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	23
DANN	Benign	0.92
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.56
MVP		0.83
MPC		0.53
ClinPred		0.064	T
GERP RS		5.8
Mutation Taster		=93/7	polymorphism

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: rs72646880; hg19: chr2-179442784; COSMIC: COSV107413239; COSMIC: COSV107413239;