rs199506676

Variant names:

• chr2-178577602-C-T
• rs199506676
• NM_001267550.2:c.68824G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178577602-C-T
• chr2-178577602-C-A
• chr2-178577602-C-G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_Moderate BP6 BS1

The NM_001267550.2(TTN):​c.68824G>A​(p.Glu22942Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000428 in 1,589,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:7
• Conservation: PhyloP100: 7.83
• 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]

ENSG00000271011 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 2-178577602-C-T is Benign according to our data. Variant chr2-178577602-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96298.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000592 (90/152130) while in subpopulation AMR AF = 0.00262 (40/15268). AF 95% confidence interval is 0.00198. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.68824G>A	p.Glu22942Lys	missense	Exon 323 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.63901G>A	p.Glu21301Lys	missense splice_region	Exon 273 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.61120G>A	p.Glu20374Lys	missense splice_region	Exon 272 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.68824G>A	p.Glu22942Lys	missense	Exon 323 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.68668G>A	p.Glu22890Lys	missense	Exon 321 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.68548G>A	p.Glu22850Lys	missense	Exon 321 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000592 AC: 90 AN: 152012 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000486

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000284 AC: 66 AN: 232160 AF XY: 0.000279

Gnomad AFR exome AF: 0.0000657

Gnomad AMR exome AF: 0.000351

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000586

Gnomad FIN exome AF: 0.0000482

Gnomad NFE exome AF: 0.000430

Gnomad OTH exome AF: 0.000896

GnomAD4 exome AF: 0.000410 AC: 590 AN: 1437754 Hom.: 0 Cov.: 35 AF XY: 0.000365 AC XY: 260 AN XY: 712738

African (AFR) AF: 0.0000310 AC: 1 AN: 32304

American (AMR) AF: 0.000735 AC: 30 AN: 40828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39260

South Asian (SAS) AF: 0.000111 AC: 9 AN: 81332

European-Finnish (FIN) AF: 0.000209 AC: 11 AN: 52700

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5646

European-Non Finnish (NFE) AF: 0.000460 AC: 507 AN: 1101304

Other (OTH) AF: 0.000523 AC: 31 AN: 59326

GnomAD4 genome AF: 0.000592 AC: 90 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.000498 AC XY: 37 AN XY: 74356

African (AFR) AF: 0.000241 AC: 10 AN: 41548

American (AMR) AF: 0.00262 AC: 40 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000486 AC: 33 AN: 67960

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000438 Hom.: 0

Bravo AF: 0.000737

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000272 AC: 1

ESP6500EA AF: 0.000367 AC: 3

ExAC AF: 0.000282 AC: 34

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Dilated cardiomyopathy 1G (3)
-	2	1	not provided (3)
-	1	1	not specified (2)
-	2	-	Primary dilated cardiomyopathy (2)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	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)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	27
DANN	Benign	0.93
Eigen	Benign	-0.037
Eigen_PC	Benign	0.071
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.19
Sift	Benign	0.19	T
Polyphen		0.16	B
Vest4		0.53
MVP		0.22
MPC		0.099
ClinPred		0.074	T
GERP RS		4.1
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.080		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: rs199506676; hg19: chr2-179442329;