rs72648972

Variant names:

• chr2-178720530-G-C
• rs72648972
• NM_001267550.2:c.23232C>G

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.23232C>G​(p.Asn7744Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,613,528 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. N7744N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (40 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 1.59
• 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=0.005209595).
• BP6: Variant 2-178720530-G-C is Benign according to our data. Variant chr2-178720530-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46715.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 = 0.00199 (303/152256) while in subpopulation SAS AF = 0.0164 (79/4810). AF 95% confidence interval is 0.0135. There are 1 homozygotes in GnomAd4. There are 167 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 40 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.23232C>G	p.Asn7744Lys	missense	Exon 80 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.22281C>G	p.Asn7427Lys	missense	Exon 78 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.19500C>G	p.Asn6500Lys	missense	Exon 77 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.23232C>G	p.Asn7744Lys	missense	Exon 80 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.23232C>G	p.Asn7744Lys	missense	Exon 80 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.22956C>G	p.Asn7652Lys	missense	Exon 78 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 301 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00407 AC: 1011 AN: 248324 AF XY: 0.00485

Gnomad AFR exome AF: 0.000711

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.000837

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00207

Gnomad OTH exome AF: 0.00449

GnomAD4 exome AF: 0.00258 AC: 3765 AN: 1461272 Hom.: 40 Cov.: 35 AF XY: 0.00310 AC XY: 2253 AN XY: 726902

African (AFR) AF: 0.000688 AC: 23 AN: 33446

American (AMR) AF: 0.00128 AC: 57 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00999 AC: 261 AN: 26120

East Asian (EAS) AF: 0.000630 AC: 25 AN: 39676

South Asian (SAS) AF: 0.0183 AC: 1581 AN: 86240

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53374

Middle Eastern (MID) AF: 0.0146 AC: 84 AN: 5760

European-Non Finnish (NFE) AF: 0.00137 AC: 1523 AN: 1111608

Other (OTH) AF: 0.00331 AC: 200 AN: 60350

GnomAD4 genome AF: 0.00199 AC: 303 AN: 152256 Hom.: 1 Cov.: 32 AF XY: 0.00224 AC XY: 167 AN XY: 74448

African (AFR) AF: 0.000722 AC: 30 AN: 41572

American (AMR) AF: 0.00124 AC: 19 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00950 AC: 33 AN: 3472

East Asian (EAS) AF: 0.000774 AC: 4 AN: 5170

South Asian (SAS) AF: 0.0164 AC: 79 AN: 4810

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00175 AC: 119 AN: 68006

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00242 Hom.: 1

Bravo AF: 0.00161

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000274 AC: 1

ESP6500EA AF: 0.00209 AC: 17

ExAC AF: 0.00436 AC: 526

Asia WGS AF: 0.00462 AC: 16 AN: 3476

EpiCase AF: 0.00186

EpiControl AF: 0.00243

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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Uncertain	0.98
Eigen	Benign	-0.13
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.87	T
PhyloP100		1.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.14
Sift	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.59		Gain of methylation at N7427 (P = 0.0259)
MVP		0.23
MPC		0.096
ClinPred		0.012	T
GERP RS		4.9
Mutation Taster		=46/54	disease causing

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: rs72648972; hg19: chr2-179585257;