rs72647876

Variant names:

• chr2-178777862-C-G
• rs72647876
• NM_001267550.2:c.4322G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178777862-C-G
• chr2-178777862-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.4322G>C​(p.Arg1441Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00955 in 1,614,030 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts 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. R1441H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0084 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0097 (82 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:29
• Conservation: PhyloP100: 7.67
• Publications: 23 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]

LOC101927055 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008319944).
• BP6: Variant 2-178777862-C-G is Benign according to our data. Variant chr2-178777862-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47046.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 = 0.00843 (1284/152296) while in subpopulation SAS AF = 0.0162 (78/4828). AF 95% confidence interval is 0.0137. There are 10 homozygotes in GnomAd4. There are 729 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.4322G>C	p.Arg1441Pro	missense	Exon 25 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.4322G>C	p.Arg1441Pro	missense	Exon 25 of 313	NP_001243779.1
	TTN	NM_133378.4		c.4322G>C	p.Arg1441Pro	missense	Exon 25 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.4322G>C	p.Arg1441Pro	missense	Exon 25 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.4322G>C	p.Arg1441Pro	missense	Exon 25 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.4046G>C	p.Arg1349Pro	missense	Exon 23 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00845 AC: 1286 AN: 152178 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.0104

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00875

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0110 AC: 2754 AN: 250888 AF XY: 0.0117

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00764

Gnomad ASJ exome AF: 0.00765

Gnomad EAS exome AF: 0.00899

Gnomad FIN exome AF: 0.0203

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.00967 AC: 14137 AN: 1461734 Hom.: 82 Cov.: 34 AF XY: 0.0100 AC XY: 7275 AN XY: 727170

African (AFR) AF: 0.00137 AC: 46 AN: 33464

American (AMR) AF: 0.00807 AC: 361 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00808 AC: 211 AN: 26130

East Asian (EAS) AF: 0.00423 AC: 168 AN: 39684

South Asian (SAS) AF: 0.0171 AC: 1472 AN: 86258

European-Finnish (FIN) AF: 0.0183 AC: 975 AN: 53414

Middle Eastern (MID) AF: 0.0137 AC: 79 AN: 5766

European-Non Finnish (NFE) AF: 0.00918 AC: 10211 AN: 1111918

Other (OTH) AF: 0.0102 AC: 614 AN: 60384

GnomAD4 genome AF: 0.00843 AC: 1284 AN: 152296 Hom.: 10 Cov.: 33 AF XY: 0.00979 AC XY: 729 AN XY: 74476

African (AFR) AF: 0.00130 AC: 54 AN: 41568

American (AMR) AF: 0.0153 AC: 234 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00894 AC: 31 AN: 3468

East Asian (EAS) AF: 0.0102 AC: 53 AN: 5180

South Asian (SAS) AF: 0.0162 AC: 78 AN: 4828

European-Finnish (FIN) AF: 0.0200 AC: 212 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00875 AC: 595 AN: 68020

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00752 Hom.: 3

Bravo AF: 0.00711

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00756 AC: 65

ExAC AF: 0.0111 AC: 1349

EpiCase AF: 0.00927

EpiControl AF: 0.0101

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	5	not provided (5)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Benign	0.96
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.40	T
PhyloP100		7.7
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.46
Sift	Benign	0.095	T
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.19
MPC		0.55
ClinPred		0.014	T
GERP RS		5.5
Mutation Taster		=92/8	polymorphism

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: rs72647876; hg19: chr2-179642589;