rs201096469

Variant names:

• chr6-25539987-C-A
• rs201096469
• NM_017640.6:c.2237C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-25539987-C-A
• chr6-25539987-C-G
• chr6-25539987-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017640.6(CARMIL1):​c.2237C>A​(p.Ala746Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000642 in 1,603,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A746V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: CARMIL1 NM_017640.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.88
• Publications: 2 publications found

Genes affected

CARMIL1 (HGNC:21581): (capping protein regulator and myosin 1 linker 1) Involved in several processes, including actin filament network formation; plasma membrane bounded cell projection organization; and positive regulation of cellular component organization. Located in several cellular components, including lamellipodium; macropinosome; and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01369223).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017640.6. 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
	CARMIL1	NM_017640.6	MANE Select	c.2237C>A	p.Ala746Glu	missense	Exon 26 of 37	NP_060110.4
	CARMIL1	NM_001173977.2		c.2237C>A	p.Ala746Glu	missense	Exon 26 of 37	NP_001167448.1	A0A8V8TRE2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARMIL1	ENST00000329474.7	TSL:1 MANE Select	c.2237C>A	p.Ala746Glu	missense	Exon 26 of 37	ENSP00000331983.6	Q5VZK9-1
	CARMIL1	ENST00000865798.1		c.2237C>A	p.Ala746Glu	missense	Exon 26 of 38	ENSP00000535857.1
	CARMIL1	ENST00000911480.1		c.2237C>A	p.Ala746Glu	missense	Exon 27 of 38	ENSP00000581539.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000159 AC: 38 AN: 238348 AF XY: 0.000131

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00327

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000457

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.0000620 AC: 90 AN: 1451286 Hom.: 0 Cov.: 30 AF XY: 0.0000541 AC XY: 39 AN XY: 721540

African (AFR) AF: 0.00 AC: 0 AN: 32924

American (AMR) AF: 0.00 AC: 0 AN: 42984

Ashkenazi Jewish (ASJ) AF: 0.00286 AC: 74 AN: 25884

East Asian (EAS) AF: 0.00 AC: 0 AN: 39102

South Asian (SAS) AF: 0.00 AC: 0 AN: 83876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00000903 AC: 10 AN: 1107642

Other (OTH) AF: 0.000100 AC: 6 AN: 59920

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74316

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000911 AC: 11

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Benign	0.28
DEOGEN2	Benign	0.0076	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.96	T
PhyloP100		2.9
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.054
Sift	Benign	0.67	T
Sift4G	Benign	1.0	T
Polyphen		0.0090	B
Vest4		0.28
MutPred		0.38		Loss of helix (P = 0.0196)
MVP		0.043
MPC		0.35
ClinPred		0.036	T
GERP RS		3.8
Varity_R		0.068
gMVP		0.45
Mutation Taster		=88/12	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: rs201096469; hg19: chr6-25540215;